This review article discusses research on transgenic Alzheimer's disease (AD) mouse models and how they are used to investigate dendritic spine structure, synaptic function, and cognition. Studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as tau pathology, contributing to both synaptic and neuronal loss. These changes in synapse structure and function, as well as outright synapse and neuron loss, underlie the neural system dysfunction that causes cognitive deficits in AD. Understanding how dementia develops in AD is crucial for developing effective therapies.
Morphological alterations to neurons of the amygdalashiraknafo
This study examined the effects of amyloid-beta (Aβ) accumulation in the amygdala of an Alzheimer's disease mouse model. The mice showed impaired fear conditioning compared to controls. While there was no neuronal loss in the lateral nucleus of the amygdala (LA), the dendritic trees and spines of LA projection neurons were morphologically altered. Specifically, plaque-free neurons in the transgenic mice had decreased large dendritic spines compared to controls. This suggests that Aβ deposition leads to structural changes in the amygdala that may underlie impaired emotional memory seen in Alzheimer's disease.
1) The study assessed changes in hippocampal dendritic spines of APP/PS1 transgenic mice, a model of Alzheimer's disease.
2) It found a substantial decrease in the frequency of large dendritic spines in plaque-free regions of the dentate gyrus in these mice compared to controls.
3) Dendrites passing through amyloid plaques also showed alterations in spine density and morphology, with lower spine density within plaques and higher density on dendrites contacting plaques.
Konstantin Ravvin: Immune Therapy Targeting Tauopathies in Alzheimer's DiseaseKonstantin Ravvin
Konstantin Ravvin: Tauopathies are diseases related to abnormal filamentous inclusions of microtubule associated protein tau commonly found across a spectrum of neurodegenerative disorders. The dissociation of monomeric tau protein from microtubule bindings sites results in the formation of aggregates with a high affinity for self-assembly. Aggregates propagate interneuronally in a prion-like fashion, resulting in widespread neuronal damage, cognitive decline and cell death. tau’s co-association with amyloid-beta in Alzheimer’s diseases makes it a potential target for therapeutic intervention. More recently, immunotherapy in passive and active forms has been shown to ameliorate amyloid load and substantially rescue cognitive impairment. Antibody-mediated tau aggregation and clearance of tau aggregates has been described in previous studies though none have evaluated the effectiveness of antibodies at substochiometric concentrations sufficient to simulate the exclusivity of the blood brain barrier. We found that substochoichiometric concentrations of antibody binding to the C-terminus of tau exacerbated aggregation as measured by ThT
fluorescence. Fibril seeds formed in the presence of antibody decreased seeding efficiency relative to non-antibody treated seeds, and end products of antibody treated seeds were
substantially more structured relative to their unseeded and normally seeded counterparts, suggesting the potential formation of novel “strains”. Antibody in the presence of normal
seeds and monomeric tau lowered seeding efficiency in a concentration dependent manner, indicating a therapeutically optimal concentration of antibody adequate enough to
decrease deplete seeding efficiency without overtly intensifying monomeric aggregation.
Konstantin Ravvin (Sackler Journal of Medicine): The Biochemical Foundations...Konstantin Ravvin
1) Alzheimer's disease is characterized by the progressive spread of amyloid beta and tau protein fibrils in the brain, resulting in neuronal death and cognitive decline.
2) Early theories proposed that a decline in acetylcholine levels played a role in Alzheimer's, but it is now thought to be a symptom rather than a cause.
3) The amyloid cascade hypothesis posits that amyloid beta plaque formation triggers tau protein tangles, which together drive neurodegeneration. However, the relationship between amyloid beta and tau remains unclear.
This document discusses hereditary metabolic disorders that affect the nervous system. It begins by introducing ataxia as a neurological sign and describing the various systems it can involve. It then categorizes inherited ataxias based on their genetic and biochemical characteristics. Specifically, it discusses acute intermittent ataxias, ataxias with polymyoclonus and seizures, ataxias with spinocerebellar dysfunction, and progressive ataxias with additional neurological signs. As examples, it provides details on Maple Syrup Urine Disease and its intermittent presentation involving ataxia, neurological symptoms, and distinctive biochemical abnormalities.
This study demonstrates that the protein MARCKS is important for maintaining the functions and barrier integrity of ependymal cells (ECs) in the brain as they age. ECs form a barrier between cerebrospinal fluid and brain tissue. The study found that MARCKS and related proteins are highly polarized in young ECs but lose their polarization as ECs age. Deleting MARCKS in ECs caused accumulation of mucins and lipids inside ECs, disrupting the barrier and inducing inflammation in surrounding brain tissue, mimicking aspects of normal aging. This suggests MARCKS is required for EC functions like mucin clearance and lipid metabolism that decline with aging and impact brain homeostasis.
The document summarizes recent research on the use of stem cells as a potential treatment for Alzheimer's disease. It discusses how neural stem cells, bone marrow stem cells, and embryonic stem cells could be used to replace damaged or dead nerve cells in the brain. However, many challenges remain for stem cells to become an effective Alzheimer's treatment, such as ensuring the cells survive, integrate properly, and target the specific brain regions affected by the disease. While promising, more research is still needed to address these issues before stem cell therapy can be applied successfully for Alzheimer's patients.
Morphological alterations to neurons of the amygdalashiraknafo
This study examined the effects of amyloid-beta (Aβ) accumulation in the amygdala of an Alzheimer's disease mouse model. The mice showed impaired fear conditioning compared to controls. While there was no neuronal loss in the lateral nucleus of the amygdala (LA), the dendritic trees and spines of LA projection neurons were morphologically altered. Specifically, plaque-free neurons in the transgenic mice had decreased large dendritic spines compared to controls. This suggests that Aβ deposition leads to structural changes in the amygdala that may underlie impaired emotional memory seen in Alzheimer's disease.
1) The study assessed changes in hippocampal dendritic spines of APP/PS1 transgenic mice, a model of Alzheimer's disease.
2) It found a substantial decrease in the frequency of large dendritic spines in plaque-free regions of the dentate gyrus in these mice compared to controls.
3) Dendrites passing through amyloid plaques also showed alterations in spine density and morphology, with lower spine density within plaques and higher density on dendrites contacting plaques.
Konstantin Ravvin: Immune Therapy Targeting Tauopathies in Alzheimer's DiseaseKonstantin Ravvin
Konstantin Ravvin: Tauopathies are diseases related to abnormal filamentous inclusions of microtubule associated protein tau commonly found across a spectrum of neurodegenerative disorders. The dissociation of monomeric tau protein from microtubule bindings sites results in the formation of aggregates with a high affinity for self-assembly. Aggregates propagate interneuronally in a prion-like fashion, resulting in widespread neuronal damage, cognitive decline and cell death. tau’s co-association with amyloid-beta in Alzheimer’s diseases makes it a potential target for therapeutic intervention. More recently, immunotherapy in passive and active forms has been shown to ameliorate amyloid load and substantially rescue cognitive impairment. Antibody-mediated tau aggregation and clearance of tau aggregates has been described in previous studies though none have evaluated the effectiveness of antibodies at substochiometric concentrations sufficient to simulate the exclusivity of the blood brain barrier. We found that substochoichiometric concentrations of antibody binding to the C-terminus of tau exacerbated aggregation as measured by ThT
fluorescence. Fibril seeds formed in the presence of antibody decreased seeding efficiency relative to non-antibody treated seeds, and end products of antibody treated seeds were
substantially more structured relative to their unseeded and normally seeded counterparts, suggesting the potential formation of novel “strains”. Antibody in the presence of normal
seeds and monomeric tau lowered seeding efficiency in a concentration dependent manner, indicating a therapeutically optimal concentration of antibody adequate enough to
decrease deplete seeding efficiency without overtly intensifying monomeric aggregation.
Konstantin Ravvin (Sackler Journal of Medicine): The Biochemical Foundations...Konstantin Ravvin
1) Alzheimer's disease is characterized by the progressive spread of amyloid beta and tau protein fibrils in the brain, resulting in neuronal death and cognitive decline.
2) Early theories proposed that a decline in acetylcholine levels played a role in Alzheimer's, but it is now thought to be a symptom rather than a cause.
3) The amyloid cascade hypothesis posits that amyloid beta plaque formation triggers tau protein tangles, which together drive neurodegeneration. However, the relationship between amyloid beta and tau remains unclear.
This document discusses hereditary metabolic disorders that affect the nervous system. It begins by introducing ataxia as a neurological sign and describing the various systems it can involve. It then categorizes inherited ataxias based on their genetic and biochemical characteristics. Specifically, it discusses acute intermittent ataxias, ataxias with polymyoclonus and seizures, ataxias with spinocerebellar dysfunction, and progressive ataxias with additional neurological signs. As examples, it provides details on Maple Syrup Urine Disease and its intermittent presentation involving ataxia, neurological symptoms, and distinctive biochemical abnormalities.
This study demonstrates that the protein MARCKS is important for maintaining the functions and barrier integrity of ependymal cells (ECs) in the brain as they age. ECs form a barrier between cerebrospinal fluid and brain tissue. The study found that MARCKS and related proteins are highly polarized in young ECs but lose their polarization as ECs age. Deleting MARCKS in ECs caused accumulation of mucins and lipids inside ECs, disrupting the barrier and inducing inflammation in surrounding brain tissue, mimicking aspects of normal aging. This suggests MARCKS is required for EC functions like mucin clearance and lipid metabolism that decline with aging and impact brain homeostasis.
The document summarizes recent research on the use of stem cells as a potential treatment for Alzheimer's disease. It discusses how neural stem cells, bone marrow stem cells, and embryonic stem cells could be used to replace damaged or dead nerve cells in the brain. However, many challenges remain for stem cells to become an effective Alzheimer's treatment, such as ensuring the cells survive, integrate properly, and target the specific brain regions affected by the disease. While promising, more research is still needed to address these issues before stem cell therapy can be applied successfully for Alzheimer's patients.
This document discusses the role of plants, environmental toxins, and physical factors in neurological disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). It notes that the geographic clustering of ALS/PD cases in areas like Guam and mutations in genes like SOD1 are interesting factors to consider. The document conducted a literature review on these topics and analyzed studies on localized incidence rates and environmental risk factors associated with certain geographic clusters. It discussed various pathological mechanisms that may be involved like oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction.
The document discusses Alzheimer's disease (AD), including its causes, symptoms, diagnosis, and treatment. It provides details on:
- AD is characterized by beta-amyloid plaques and tau neurofibrillary tangles in the brain that lead to nerve cell death. Genetic and lifestyle factors may contribute to causes.
- Symptoms progress from mild memory loss to severe cognitive decline and inability for self-care. Stages include mild, moderate, and severe.
- Diagnosis involves assessing cognitive impairment and ruling out other conditions. Imaging and neurological tests are also used.
- Current treatments aim to slow progression and manage symptoms. These include cholinesterase inhibitors and memantine which increase
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
This study investigated apoptosis in a transgenic mouse model of ALS. The researchers found:
1) DNA fragmentation, a marker of apoptosis, was significantly higher in the brain regions of mice expressing a mutant SOD1 gene compared to control mice, as shown by TUNEL staining and ELISA assays.
2) Double staining showed many TUNEL-positive motoneurons and glial cells in the spinal cord and brainstem of mutant SOD1 mice, but not controls.
3) Electron microscopy confirmed neuronal and glial apoptosis in these regions through characteristic morphological features in mutant SOD1 mice.
4) TUNEL-positive neurons were also observed in the motor and sensory cortices of mutant
This poster abstract proposes a new depurative strategy to potentially reduce or delay some spinal cord and brain degenerative and inflammatory conditions. It discusses using an informatics approach and Turing machine theory to develop an algorithm that can translate needs into a practical therapeutic hypothesis. Specifically, it suggests applying concepts from depurative toxicology procedures used to reduce blood toxicity to the brain and spinal cord's "wasting system" to help remove pathological catabolic substances implicated in neurodegenerative diseases. The goal is to delay disease progression through effective removal of toxins while avoiding additional toxicity or damage.
Pharmacological neuroprotection in blinding eye diseasesAlexander Decker
This document summarizes research on using calcium channel blockers for neuroprotection in blinding eye diseases like glaucoma and retinitis pigmentosa. It discusses how calcium channel blockers may prevent apoptosis of retinal ganglion cells and photoreceptors by reducing intracellular calcium levels. The review evaluates evidence from studies that calcium channel blockers like nimodipine may increase ocular blood flow, enhance retinal ganglion cell survival, and show neuroprotective effects in animal models of hypoxia and retinal disease. It concludes that calcium channel blockers represent a potential pharmacological strategy for neuroprotection in glaucoma and retinitis pigmentosa but that more randomized controlled clinical trials are still needed.
Hypothetical model of dynamic biomarkers of the alzheimer pathological cascadeCarolinaRamrez60
The document presents a hypothetical model of biomarkers for Alzheimer's disease progression. It proposes that:
1) Abnormal amyloid beta processing occurs first, before symptoms, which is detected by reduced CSF Aβ42 and increased amyloid PET tracer retention.
2) After a lag period, neuronal dysfunction and neurodegeneration become dominant, detected by increased CSF tau and brain atrophy on structural MRI.
3) Neurodegeneration is accompanied by synaptic dysfunction detected by decreased fluorodeoxyglucose uptake on PET.
4) The model relates disease stage to biomarkers, with amyloid biomarkers becoming abnormal first before neurodegenerative biomarkers and symptoms, which then correlate with severity.
Leaky Blood-Brain Barrier a Harbinger of Alzheimer s Disease - presentation made at Alzforum's live webinar of February 17, 2015. See details at: http://www.alzforum.org/webinars/leaky-blood-brain-barrier-harbinger-alzheimers
This document discusses various materials and therapies for peripheral nerve regeneration. It covers guidance therapies using nerve conduits made from natural and synthetic biomaterials. Biomolecular therapies involve delivering growth factors to promote regeneration. Cellular therapies utilize Schwann cells, stem cells, and genetically modified cells. Advanced techniques include nerve conduits fabricated using 3D printing, injection molding and aligned polymer fibers. Future areas of focus are multi-chamber conduits and stem cell therapies to further enhance regeneration.
1) Researchers screened 40,000 compounds and identified TRO19622 as a potential drug candidate for treating amyotrophic lateral sclerosis (ALS).
2) In vitro, TRO19622 promoted motor neuron survival in a dose-dependent manner and rescued motor neurons from death.
3) In animal models of ALS and nerve damage, TRO19622 improved motor performance, delayed disease onset, extended survival, and promoted nerve regeneration.
This document summarizes a book titled "Role of Plants, environmental toxins and physical neurotoxicological factors in Amyotrophic lateral sclerosis, Alzheimer Disease and Other Neurodegenerative Diseases." It has 10 authors from various countries. The book aims to observe the effects of plant neurotoxins, physical factors, and geography on neurodegenerative diseases like ALS, PD, and AD. It reviews literature on geographic clusters of these diseases and genetic mutations. It also discusses the brain's high metabolic needs, interactions between neurons and astrocytes, and how impairments in these systems can lead to neurodegeneration. The book presents figures and intends to develop new hypotheses and therapies based on contributing pathogenic factors.
Marc Dhenain Alzforum Webinar - Dec 7, 2016Alzforum
Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/
Presentation made by Jernej Ule on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
This study aimed to develop CRISPR/Cas9 magnetoplexes that can guide the CRISPR/Cas9 system to the heart for gene editing to improve cardiac repair after a myocardial infarction. The objectives were to develop these magnetoplexes and demonstrate their ability to target the miR34a gene in a mouse model of MI. The methods used included immunocytochemistry, RNA isolation and qRT-PCR, Western blot analysis, and Sanger sequencing. The results showed the magnetoplexes successfully introduced the CRISPR/Cas9 vector and reduced expression of miR34a and Caspase 3 while increasing expression of Notch1 and pnuts. The discussion concluded the objectives were achieved and knockout
Akhtar and Breunig-2015-Frontiers in Cellular Neuroscience - Barriers to post...Aslam Akhtar, MS
This document summarizes barriers to postnatal neurogenesis in the cerebral cortex. It describes how the cortex develops prenatally through tightly regulated neurogenesis along radial glial scaffolds. After birth, radial glia are depleted and the "gliogenic switch" stops neurogenesis in favor of gliogenesis. As a result, the adult cortex has very little ability to replace neurons lost to injury or disease. Strategies to promote postnatal neurogenesis, such as interneuron transplantation and glial reprogramming, aim to circumvent the developmental barriers normally preventing regeneration in the adult brain.
The document discusses how microbial interactions with the blood-brain barrier (BBB) endothelium can modulate astroglial and neuronal function. It describes the BBB endothelium as part of the neurovascular unit, where homeostasis is maintained through interactions between endothelial, neuronal and glial cells. Dysfunction in any component can affect the others and contribute to neurological disease. The role of BBB endothelial activation in disease is unclear. In vitro BBB models are useful for studying these interactions but may not fully reflect the in vivo environment. Some pathogens like Plasmodium falciparum, which causes cerebral malaria, can induce neurological symptoms without crossing the BBB by activating the endothelium. Release of factors from the activated endothelium towards the brain may then affect
Aminah Sheikh's research focuses on understanding the neural mechanisms underlying abnormal brain development that result from early brain injuries. Using a neonatal rat model of hypoxia-ischemia, she investigates how these injuries damage subplate neurons in the developing brain and alter the maturation of brain circuits. Her work aims to identify targets for therapies to prevent long-term cognitive impairment resulting from neonatal brain damage.
CODAS syndrome is a rare multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. The researchers identified four mutations in the LONP1 gene in ten individuals with CODAS syndrome from three ancestral backgrounds. LONP1 encodes the mitochondrial Lon protease, which is involved in protein quality control and respiratory complex assembly in mitochondria. The mutations cluster in the AAA+ domain near the ATP-binding pocket and result in defects in ATP-dependent proteolysis. Lymphoblastoid cell lines from affected individuals show swollen mitochondria, aggregated cytochrome c oxidase subunit II, and reduced mitochondrial function, linking LONP1 mutations to CODAS syndrome.
Volcanoes form as molten rock, known as magma, rises from below the Earth's crust and erupts at the surface. The composition and viscosity of the magma determines the type of eruption, from gentle to violent explosive eruptions. During an eruption, molten rock (lava), rock fragments of varying sizes, and volcanic gases are ejected from the volcano. The largest rock fragments fall closest to the volcano, while very fine ash can travel much farther and remain suspended in the air for long periods of time. Most volcanic activity occurs at plate boundaries in the oceans, but some volcanoes form independently at hotspots in the crust.
The challenge of the end of-life discussion housestaff 2014pkhohl
The document discusses end-of-life care for cancer patients in the United States. It finds that about 1/3 of patients with poor prognosis cancer spend their last days in hospitals and intensive care units. About 10% receive aggressive life-sustaining treatments near death. Use of hospice care varies widely between regions and hospitals, with some providing little or no hospice support. Early discussions about end-of-life care can help patients receive less aggressive care near death that aligns with their goals and values, and helps caregivers cope after death. However, patients have difficulty accepting terminal prognoses, and interventions simply providing prognostic information have not impacted care received or understanding on their own. A long-term process
PIAGET y VYGOTSKI tenían diferencias en cuanto a la relación entre el pensamiento y el lenguaje. Para PIAGET, el pensamiento se desarrolla a partir de la función simbólica, mientras que para VYGOTSKI depende de la interacción social. Ambos concuerdan en que el lenguaje provee herramientas para el pensamiento, aunque difieren en si es egocéntrico u obtiene primero su forma social.
Richard Dyer's star theory states that celebrities are constructed images meant to appeal to audiences and make money. A performer becomes a star when their persona is publicized beyond just their music. Dyer identifies four aspects of star construction: stars as constructions, where celebrities are artificial images with unique selling points; industry and audience, where record companies shape stars to appeal to target demographics; ideology and culture, where stars promote beliefs to audiences; and character and personality, where public personas are based on generations and conform to audiences. The document uses Justin Bieber as an example, analyzing how his image and persona have been constructed over time across these four areas to maximize his appeal and profits.
This document discusses the role of plants, environmental toxins, and physical factors in neurological disorders such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD). It notes that the geographic clustering of ALS/PD cases in areas like Guam and mutations in genes like SOD1 are interesting factors to consider. The document conducted a literature review on these topics and analyzed studies on localized incidence rates and environmental risk factors associated with certain geographic clusters. It discussed various pathological mechanisms that may be involved like oxidative stress, glutamate excitotoxicity, and mitochondrial dysfunction.
The document discusses Alzheimer's disease (AD), including its causes, symptoms, diagnosis, and treatment. It provides details on:
- AD is characterized by beta-amyloid plaques and tau neurofibrillary tangles in the brain that lead to nerve cell death. Genetic and lifestyle factors may contribute to causes.
- Symptoms progress from mild memory loss to severe cognitive decline and inability for self-care. Stages include mild, moderate, and severe.
- Diagnosis involves assessing cognitive impairment and ruling out other conditions. Imaging and neurological tests are also used.
- Current treatments aim to slow progression and manage symptoms. These include cholinesterase inhibitors and memantine which increase
1) ALS is a progressive neurodegenerative disease that affects motor neurons, leading to muscle paralysis. It was first described in 1874 but its pathogenesis remains unclear.
2) ALS may be caused by both increased toxicity from substances like RNA proteins and weakness of the motor neuron system. Genetic mutations and environmental toxins are also implicated in some cases.
3) The document proposes new experimental and drug delivery approaches to better understand disease mechanisms and improve treatment of ALS.
This study investigated apoptosis in a transgenic mouse model of ALS. The researchers found:
1) DNA fragmentation, a marker of apoptosis, was significantly higher in the brain regions of mice expressing a mutant SOD1 gene compared to control mice, as shown by TUNEL staining and ELISA assays.
2) Double staining showed many TUNEL-positive motoneurons and glial cells in the spinal cord and brainstem of mutant SOD1 mice, but not controls.
3) Electron microscopy confirmed neuronal and glial apoptosis in these regions through characteristic morphological features in mutant SOD1 mice.
4) TUNEL-positive neurons were also observed in the motor and sensory cortices of mutant
This poster abstract proposes a new depurative strategy to potentially reduce or delay some spinal cord and brain degenerative and inflammatory conditions. It discusses using an informatics approach and Turing machine theory to develop an algorithm that can translate needs into a practical therapeutic hypothesis. Specifically, it suggests applying concepts from depurative toxicology procedures used to reduce blood toxicity to the brain and spinal cord's "wasting system" to help remove pathological catabolic substances implicated in neurodegenerative diseases. The goal is to delay disease progression through effective removal of toxins while avoiding additional toxicity or damage.
Pharmacological neuroprotection in blinding eye diseasesAlexander Decker
This document summarizes research on using calcium channel blockers for neuroprotection in blinding eye diseases like glaucoma and retinitis pigmentosa. It discusses how calcium channel blockers may prevent apoptosis of retinal ganglion cells and photoreceptors by reducing intracellular calcium levels. The review evaluates evidence from studies that calcium channel blockers like nimodipine may increase ocular blood flow, enhance retinal ganglion cell survival, and show neuroprotective effects in animal models of hypoxia and retinal disease. It concludes that calcium channel blockers represent a potential pharmacological strategy for neuroprotection in glaucoma and retinitis pigmentosa but that more randomized controlled clinical trials are still needed.
Hypothetical model of dynamic biomarkers of the alzheimer pathological cascadeCarolinaRamrez60
The document presents a hypothetical model of biomarkers for Alzheimer's disease progression. It proposes that:
1) Abnormal amyloid beta processing occurs first, before symptoms, which is detected by reduced CSF Aβ42 and increased amyloid PET tracer retention.
2) After a lag period, neuronal dysfunction and neurodegeneration become dominant, detected by increased CSF tau and brain atrophy on structural MRI.
3) Neurodegeneration is accompanied by synaptic dysfunction detected by decreased fluorodeoxyglucose uptake on PET.
4) The model relates disease stage to biomarkers, with amyloid biomarkers becoming abnormal first before neurodegenerative biomarkers and symptoms, which then correlate with severity.
Leaky Blood-Brain Barrier a Harbinger of Alzheimer s Disease - presentation made at Alzforum's live webinar of February 17, 2015. See details at: http://www.alzforum.org/webinars/leaky-blood-brain-barrier-harbinger-alzheimers
This document discusses various materials and therapies for peripheral nerve regeneration. It covers guidance therapies using nerve conduits made from natural and synthetic biomaterials. Biomolecular therapies involve delivering growth factors to promote regeneration. Cellular therapies utilize Schwann cells, stem cells, and genetically modified cells. Advanced techniques include nerve conduits fabricated using 3D printing, injection molding and aligned polymer fibers. Future areas of focus are multi-chamber conduits and stem cell therapies to further enhance regeneration.
1) Researchers screened 40,000 compounds and identified TRO19622 as a potential drug candidate for treating amyotrophic lateral sclerosis (ALS).
2) In vitro, TRO19622 promoted motor neuron survival in a dose-dependent manner and rescued motor neurons from death.
3) In animal models of ALS and nerve damage, TRO19622 improved motor performance, delayed disease onset, extended survival, and promoted nerve regeneration.
This document summarizes a book titled "Role of Plants, environmental toxins and physical neurotoxicological factors in Amyotrophic lateral sclerosis, Alzheimer Disease and Other Neurodegenerative Diseases." It has 10 authors from various countries. The book aims to observe the effects of plant neurotoxins, physical factors, and geography on neurodegenerative diseases like ALS, PD, and AD. It reviews literature on geographic clusters of these diseases and genetic mutations. It also discusses the brain's high metabolic needs, interactions between neurons and astrocytes, and how impairments in these systems can lead to neurodegeneration. The book presents figures and intends to develop new hypotheses and therapies based on contributing pathogenic factors.
Marc Dhenain Alzforum Webinar - Dec 7, 2016Alzforum
Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/
Presentation made by Jernej Ule on the 20th of April, 2017, at the live webinar hosted by Alzforum: http://www.alzforum.org/webinars/webinar-cortex-aging-too-fast-blame-tmem106b-and-progranulin
This study aimed to develop CRISPR/Cas9 magnetoplexes that can guide the CRISPR/Cas9 system to the heart for gene editing to improve cardiac repair after a myocardial infarction. The objectives were to develop these magnetoplexes and demonstrate their ability to target the miR34a gene in a mouse model of MI. The methods used included immunocytochemistry, RNA isolation and qRT-PCR, Western blot analysis, and Sanger sequencing. The results showed the magnetoplexes successfully introduced the CRISPR/Cas9 vector and reduced expression of miR34a and Caspase 3 while increasing expression of Notch1 and pnuts. The discussion concluded the objectives were achieved and knockout
Akhtar and Breunig-2015-Frontiers in Cellular Neuroscience - Barriers to post...Aslam Akhtar, MS
This document summarizes barriers to postnatal neurogenesis in the cerebral cortex. It describes how the cortex develops prenatally through tightly regulated neurogenesis along radial glial scaffolds. After birth, radial glia are depleted and the "gliogenic switch" stops neurogenesis in favor of gliogenesis. As a result, the adult cortex has very little ability to replace neurons lost to injury or disease. Strategies to promote postnatal neurogenesis, such as interneuron transplantation and glial reprogramming, aim to circumvent the developmental barriers normally preventing regeneration in the adult brain.
The document discusses how microbial interactions with the blood-brain barrier (BBB) endothelium can modulate astroglial and neuronal function. It describes the BBB endothelium as part of the neurovascular unit, where homeostasis is maintained through interactions between endothelial, neuronal and glial cells. Dysfunction in any component can affect the others and contribute to neurological disease. The role of BBB endothelial activation in disease is unclear. In vitro BBB models are useful for studying these interactions but may not fully reflect the in vivo environment. Some pathogens like Plasmodium falciparum, which causes cerebral malaria, can induce neurological symptoms without crossing the BBB by activating the endothelium. Release of factors from the activated endothelium towards the brain may then affect
Aminah Sheikh's research focuses on understanding the neural mechanisms underlying abnormal brain development that result from early brain injuries. Using a neonatal rat model of hypoxia-ischemia, she investigates how these injuries damage subplate neurons in the developing brain and alter the maturation of brain circuits. Her work aims to identify targets for therapies to prevent long-term cognitive impairment resulting from neonatal brain damage.
CODAS syndrome is a rare multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. The researchers identified four mutations in the LONP1 gene in ten individuals with CODAS syndrome from three ancestral backgrounds. LONP1 encodes the mitochondrial Lon protease, which is involved in protein quality control and respiratory complex assembly in mitochondria. The mutations cluster in the AAA+ domain near the ATP-binding pocket and result in defects in ATP-dependent proteolysis. Lymphoblastoid cell lines from affected individuals show swollen mitochondria, aggregated cytochrome c oxidase subunit II, and reduced mitochondrial function, linking LONP1 mutations to CODAS syndrome.
Volcanoes form as molten rock, known as magma, rises from below the Earth's crust and erupts at the surface. The composition and viscosity of the magma determines the type of eruption, from gentle to violent explosive eruptions. During an eruption, molten rock (lava), rock fragments of varying sizes, and volcanic gases are ejected from the volcano. The largest rock fragments fall closest to the volcano, while very fine ash can travel much farther and remain suspended in the air for long periods of time. Most volcanic activity occurs at plate boundaries in the oceans, but some volcanoes form independently at hotspots in the crust.
The challenge of the end of-life discussion housestaff 2014pkhohl
The document discusses end-of-life care for cancer patients in the United States. It finds that about 1/3 of patients with poor prognosis cancer spend their last days in hospitals and intensive care units. About 10% receive aggressive life-sustaining treatments near death. Use of hospice care varies widely between regions and hospitals, with some providing little or no hospice support. Early discussions about end-of-life care can help patients receive less aggressive care near death that aligns with their goals and values, and helps caregivers cope after death. However, patients have difficulty accepting terminal prognoses, and interventions simply providing prognostic information have not impacted care received or understanding on their own. A long-term process
PIAGET y VYGOTSKI tenían diferencias en cuanto a la relación entre el pensamiento y el lenguaje. Para PIAGET, el pensamiento se desarrolla a partir de la función simbólica, mientras que para VYGOTSKI depende de la interacción social. Ambos concuerdan en que el lenguaje provee herramientas para el pensamiento, aunque difieren en si es egocéntrico u obtiene primero su forma social.
Richard Dyer's star theory states that celebrities are constructed images meant to appeal to audiences and make money. A performer becomes a star when their persona is publicized beyond just their music. Dyer identifies four aspects of star construction: stars as constructions, where celebrities are artificial images with unique selling points; industry and audience, where record companies shape stars to appeal to target demographics; ideology and culture, where stars promote beliefs to audiences; and character and personality, where public personas are based on generations and conform to audiences. The document uses Justin Bieber as an example, analyzing how his image and persona have been constructed over time across these four areas to maximize his appeal and profits.
The document outlines an agenda for a workshop called "The Lecture is Dead. Long Live the Lecture!" which aims to teach more engaging presentation methods. It discusses challenges with traditional lectures and working memory. Various presentation techniques are presented that focus on storytelling, interaction, and concise delivery of essential information like the Pecha Kucha and Ignite formats. The goal is to help students acquire information in a more brain-friendly way compared to standard lectures.
The document discusses different perspectives on education. It questions what skills and values schools hope to instill in students. It also examines how the internet has influenced reading habits and media, and whether critical thinking can be developed through subjects like literature, math and history or by focusing on skills like problem-solving. The document explores debates around balancing subjects like dance, art and music with core academics, and redefining what it means to be well-educated today.
This document contains a collection of images, phrases, and short passages on various topics related to education, including integration, disruptive innovation, the power of free, budget cuts, student learning, classroom technology use, and defining literacy. It touches on several themes but does not provide a clear overall message or argument.
This study analyzed dendritic spine morphology in the CA1 region of the hippocampus in a mouse model of Alzheimer's disease (AD). Three key findings were observed:
1) Dendritic spine necks in the stratum oriens layer were significantly shorter in AD mice compared to controls.
2) The frequency of dendritic spines with small head volumes increased in the stratum radiatum layer of AD mice.
3) These layer-specific changes to spine morphology in an AD mouse model may underlie the synaptic dysfunction and cognitive impairments seen in the disease. The changes reflect the effects of amyloid-beta overexpression on excitatory synapses in the hippocampus.
Adult Neurogenesis and it's Role in Alzheimer'sAbhishek Das
This document summarizes adult neurogenesis and its role in brain disorders such as Alzheimer's disease. It describes how new neurons are generated from neural stem cells in the subventricular zone and hippocampus of the adult brain. Alterations in neurogenesis are linked to neurological conditions like Alzheimer's, where neurofibrillary tangles and amyloid plaques accumulate and neurons die, affecting areas like the hippocampus early on. Efforts are underway to understand how neurogenesis contributes to disease and potentially harness neural stem cells to help repair symptoms.
Abhishek Das_20131056_BIO334_Adult Neurogenesis_RevisedAbhishek Das
This document summarizes adult neurogenesis and its role in brain disorders such as Alzheimer's disease. It describes how new neurons are generated from neural stem cells in the subventricular zone and hippocampus of the adult brain. Alterations in neurogenesis are linked to neurological conditions - decreased neurogenesis is associated with Alzheimer's disease, where neurofibrillary tangles and amyloid plaques accumulate and cause neuronal death. Efforts are being made to understand how neurogenesis contributes to disease and potentially harness neural stem cells to help repair symptoms.
This document discusses perspectives in molecular imaging and immunotherapies for Alzheimer's disease (AD). It provides background on AD, reviewing current theories for its pathogenesis including the cholinergic, amyloid-beta, and tau hypotheses. Imaging technologies like positron emission tomography (PET) and magnetic resonance imaging (MRI) can help with early diagnosis by detecting biomarkers for different stages of AD in cerebrospinal fluid and brain tissue. Combining molecular imaging systems may improve accuracy. Current and future immunotherapies aim to treat or prevent AD by targeting its underlying molecular mechanisms.
This document summarizes a study on developing a novel protein interaction platform to study neurodegeneration. The study cultured neuronal stem cells to form neurospheres, which were used as a model system. Lentiviral transfection was optimized to introduce target genes stably into the neurospheres. The goal was to analyze protein interactions of Alzheimer's disease proteins by co-immunoprecipitation of neurosphere cultures expressing tagged target proteins. This model aims to further the understanding of molecular mechanisms in neurodegenerative disorders like Alzheimer's disease.
1) Alzheimer's disease is characterized by progressive cognitive decline associated with the propagation of amyloid-beta and tau protein fibrils in the brain, resulting in neuronal death.
2) The cholinergic hypothesis proposes that depleted levels of acetylcholine in the brain, particularly in areas responsible for memory and cognition, contribute to Alzheimer's symptoms. However, acetylcholine decline may be a symptom rather than a cause of neurodegeneration.
3) The amyloid cascade hypothesis posits that amyloid-beta plaque formation triggers tau protein tangle formation, driving the progression of Alzheimer's pathology and neurodegeneration.
The Main Molecular Bases of Amyotrophic Lateral Sclerosis: An Integrating Reviewasclepiuspdfs
Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that affects the lower and upper motor neurons. Its etiology is unknown, despite several studies that point to risk factors and genetic for the disease. It does not have a definitive treatment and the diagnosis, most of the time, is time consuming and demands varied criteria for adequate definition and classification. In the search for new treatments, gene therapy with gene insertion aims to reduce the impact of ALS on the patient. The study of molecular basis as the root cause of the disease becomes necessary to advance the discovery of effective treatment and a rapid diagnosis, aiming at improving the quality of life of the ALS patients. Therefore, the present work had the objective to bring an update of the literature on ALS, as well as to describe the main molecular bases involved in the causative/causative process of this disease.
This document discusses the evolutionary perspective on neurodegenerative diseases like Parkinson's disease (PD). It proposes that PD is uniquely human because of the massive expansion of dopamine neurons in the human brain compared to other mammals. This neuronal overload may explain the selective fragility seen in PD. While no spontaneous movement disorders are seen in other mammals, useful animal models of PD exist. Reasons for the increasing prevalence of PD in humans over history include longer lifespans and reduced physical activity levels impacting neurotrophic factors. Brain evolution in vertebrates led to increased complexity and new structures, which may have created vulnerabilities underlying certain neurodegenerative diseases.
This document discusses Apolipoprotein E4 (ApoE4), which is the greatest known genetic risk factor for Alzheimer's disease (AD). It provides background on AD, including its clinical diagnosis criteria of neurofibrillary tangles and neuritic plaques. It discusses early-onset familial AD caused by mutations increasing amyloid-beta production, and late-onset sporadic AD which is associated with ApoE4 polymorphisms. ApoE4 is hypothesized to promote amyloid-beta fibril formation and decrease age of AD onset. The document focuses on explaining the role of ApoE4 in the pathogenesis of late-onset AD.
A Proposed Mechanism for Autoimmune Mediated Motor Dysfunctions, and a Hypoth...ramdab
A research study involving autoantibodies, PANDAS, autism, anti-brain antibodies, proteomics, choreas, thalamocortical pathways, ADHD, streptococcus and a wonderful research subject who makes her parents proud every day.
Chronic Neuroinflammation in Alzheimer’s Disease New Perspectives Animal Mode...Niloo Karunaweera
This review article discusses chronic neuroinflammation in Alzheimer's disease and potential new animal models and drug candidates. Specifically:
1) Chronic neuroinflammation is now considered a major factor in Alzheimer's pathogenesis, but current transgenic animal models do not fully replicate the degree of inflammation, neurodegeneration, and cognitive decline seen in humans.
2) A new potential animal model is the GFAP-IL6 mouse, which shows substantial neurodegeneration, motor/cognitive decline from 6 months, mimicking human Alzheimer's features better than existing models.
3) Three candidate drugs - curcumin, apigenin, and tenilsetam - are proposed that could be tested in this new animal model to
- The study analyzed Alzheimer's disease pathology and expression of the nuclear receptor Nurr1 in 5XFAD mice, a model of severe amyloidosis and neuronal death.
- In the subiculum region of the hippocampus, amyloid plaques and microgliosis increased with age in 5XFAD mice. Significant neuronal loss occurred by 4 months of age.
- Nurr1 expression, which plays a neuroprotective role, decreased in the hippocampus of 5XFAD mice compared to controls by 4 months. Nurr1 was mainly expressed in neurons.
A presentation about Alzheimer's disease, it's definition, it's etiology, its mechanism of development as well as actual treatment and developing treatments.
A New Perspective On Alzheimer S Disease As A Brain Expression Of A Complex M...Tony Lisko
This document discusses Alzheimer's disease as a brain expression of a complex metabolic disorder. It summarizes that AD is characterized by abnormalities at systemic, histological, macromolecular and biochemical levels beyond amyloid plaques and neurofibrillary tangles. It proposes that cerebral hypoperfusion and metabolic stress from factors like atherosclerosis, infections and insulin resistance can trigger AD pathology by inducing oxidative damage and impairing brain energy metabolism. Specifically, it suggests that arginine and branched chain amino acid metabolism disturbances contribute to AD pathogenesis and that maintaining adequate levels of these nutrients may have therapeutic potential.
The cytoskeleton plays a key role in maintaining neuronal shape and function. A recent study found alterations in the expression of beta tubulin isoforms in brain regions of schizophrenia patients. Specifically, beta tubulin expression was decreased in the anterior cingulate cortex and increased in the dorsolateral prefrontal cortex of schizophrenia patients compared to controls. The neuronal cytoskeleton, comprised of microtubules, intermediate filaments, and microfilaments, is involved in transporting proteins and organelles within neurons and maintaining cell structure. Abnormalities in the cytoskeleton are associated with neurodegenerative diseases and psychiatric illnesses.
This document discusses a proposed theory using Turing machines to develop a new therapeutic strategy for treating some spinal cord and brain conditions using a depurative-toxicological-pharmacological approach. It reviews literature on neurodegenerative diseases like Alzheimer's, Parkinson's, and ALS to understand common pathological mechanisms involving accumulation of toxic metabolic byproducts that the central nervous system lacks efficient means of removing. The theory aims to translate these insights into a practical hypothesis for reducing or delaying disease progression. The document also summarizes findings from studies showing cerebrospinal fluid from progressive multiple sclerosis patients causes mitochondrial dysfunction in neurons, identifying a potential biological mechanism and therapeutic target for progressive forms of the disease.
- Alzheimer's disease is a genetic and neurologic disorder that causes brain cells to die and the brain to shrink, resulting in the loss of cognitive skills. It is caused by the accumulation of beta-amyloid plaques and tau proteins in the brain due to genetic mutations.
- Key parts of the brain affected include the hippocampus, entorhinal cortex, and cerebral cortex. The hippocampus is involved in memory, the entorhinal cortex is an information pathway, and the cerebral cortex controls behavior and reasoning.
- Alzheimer's was first identified in 1907 by Alois Alzheimer and is characterized by a deterioration of cognitive functions over 5-12 years that can now be detected using brain imaging, clinical tests, and
This study examines changes in dendritic branching and spines in the frontal, temporal, and parietal cortex from individuals diagnosed as non-cognitively impaired (NCI), with mild cognitive impairment (MCI), or with Alzheimer's disease (AD). Brain tissue was analyzed using the Golgi impregnation method to quantify dendritic branching and spines. Results showed each cortical region had distinct patterns of dendritic changes from NCI to MCI to AD. The temporal cortex saw a 20% loss of branching in MCI and a further 5% loss in AD. The parietal cortex had a mild 4% loss in MCI and a 10% loss in AD. In contrast, the frontal cortex showed a
1) Alzheimer's disease is a progressive brain disorder that destroys memory and thinking skills. It was first described by Alois Alzheimer in 1906 and is the most common form of dementia.
2) The disease is characterized by beta-amyloid plaques and tau protein tangles that build up in the brain, resulting in the loss of connections between neurons and death of brain cells. This leads to the symptoms of impaired memory, thinking, and behavior.
3) While the causes of Alzheimer's are not fully known, genetic and environmental factors are believed to play a role. Risk increases significantly with age, though early-onset Alzheimer's can occur much earlier. There is currently no cure for the disease.
This document discusses Alzheimer's disease, including its causes, symptoms, stages of progression, diagnosis, current treatments, and potential new treatments in development. Specifically, it describes how Alzheimer's is characterized by beta-amyloid plaque and tau protein tangle buildup in the brain, outlines the four stages of the disease and their symptoms, and discusses several FDA-approved medications commonly used to treat symptoms, including Aricept, Exelon, Razadyne, and Namenda. It also mentions two new compounds in clinical trials, a beta-secretase inhibitor and NIC5-15, that may help slow the disease's progression.
Similar to Spines, plasticity, and cognition in alzheimer model mice. (20)
This chapter discusses the amygdala in Alzheimer's disease (AD). It notes that the amygdala is severely affected by AD pathology and is involved in emotional processing. Damage to the amygdala in AD leads to neuropsychiatric symptoms like anxiety and personality changes in patients. Studies also show impaired emotional memory in AD patients that correlates with amygdala atrophy. Autopsies reveal neurofibrillary tangles, amyloid plaques and neuronal loss in the amygdala of AD patients. Imaging studies further demonstrate amygdala volume reductions in AD patients, even in early stages, associated with cognitive impairment.
1. The study found that NMDA receptor activation triggers an association between the tumor suppressor protein PTEN and the synaptic scaffolding protein PSD-95.
2. This association requires a PDZ-binding motif on PTEN and leads to PTEN being recruited to and anchored at dendritic spines.
3. Enhancing PTEN's lipid phosphatase activity was found to specifically drive depression of AMPA receptor-mediated synaptic responses, and this activity was required for NMDA receptor-dependent long-term depression (LTD) but not other forms of plasticity.
This document summarizes a study that found phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) is continuously required to maintain AMPA receptor clustering at the postsynaptic membrane, which is necessary for sustaining synaptic function. The study manipulated PIP3 levels in hippocampal neurons and found that reducing PIP3 impaired the accumulation of PSD-95 in spines and caused AMPA receptors to become more mobile and migrate away from the postsynaptic density, leading to synaptic depression over time. Therefore, constant low-level turnover of PIP3 at synapses is required to maintain AMPA receptor clustering and synaptic strength under normal conditions.
WIP is a negative regulator of neuronal maturation and synaptic activity. Mice lacking WIP (WIP-/-) have enlarged neuronal somas and overgrown neuritic and dendritic branches, especially during early development. WIP-/- neurons also have increased amplitude and frequency of miniature excitatory postsynaptic currents, indicating more mature synapses than in wild-type neurons. This reveals WIP as a previously unknown regulator of neuronal maturation and synaptic activity.
1) A peptide called FGL enhances learning and memory in rodents by stimulating the delivery of glutamate receptors to synapses, strengthening synaptic transmission. This effect is mediated through the activation of protein kinase C.
2) FGL treatment heightens the induction of long-term potentiation in response to synaptic activity, improving the encoding of information.
3) FGL is poised to begin clinical trials this year for Alzheimer's disease, as prior studies show it improves memory and reduces neuropathology in rodent models of AD.
This document summarizes research investigating the cellular and molecular mechanisms underlying cognitive enhancement induced by a peptide called FGL. The key findings are:
1. FGL activates fibroblast growth factor receptor (FGFR) signaling pathways in vivo and in vitro.
2. FGL enhances long-term potentiation (LTP) in hippocampal slices by facilitating delivery of AMPA receptors to synapses through activation of NMDA receptors.
3. Both the LTP enhancement and cognitive improvement produced by FGL are mediated by initial protein kinase C (PKC) activation followed by sustained calcium/calmodulin-dependent protein kinase II (CaMKII) activation.
4. These results link facilitation
1) The document discusses common intracellular signaling pathways that are involved in both growth/differentiation processes early in development and synaptic plasticity in mature neurons.
2) Two examples are described in detail: the Ras-PI3K pathway and signaling elicited by neural cell adhesion molecules (NCAMs) interacting with growth factor receptors.
3) For the Ras-PI3K pathway, calcium entry via NMDA receptors can activate Ras, which then activates PI3K to produce PIP3 and drive LTP. Alternatively, NMDA receptors can activate Rap proteins to induce PTEN, reduce PIP3, and drive LTD.
1. The study used high-resolution fluorescence recovery after photobleaching (FRAP) to examine the dynamics and organization of AMPA receptors (AMPARs) within the postsynaptic density (PSD) of single dendritic spines in cultured hippocampal neurons.
2. They found that under basal conditions, AMPARs showed limited lateral diffusion within the PSD, but clustered together in a matrix that continuously reshaped in an actin-dependent manner.
3. Application of glutamate increased the intrasynaptic mobility of AMPARs, suggesting activated synapses promote exchange of receptors among subdomains. This supports the idea that the PSD regulates subsynaptic receptor distribution.
This article reviews studies on transgenic Alzheimer's disease (AD) mouse models that investigate dendritic spine structure, synaptic function, and cognition. These studies show that soluble amyloid-beta initiates synaptic dysfunction and loss, as well as pathological changes in tau, which contribute to both synaptic and neuronal loss. In vivo imaging reveals plaque-associated spine loss and structural plasticity deficits in AD mouse models. Synaptic plasticity is also severely impaired in AD mouse models, with deficits in basal synaptic transmission and long-term potentiation emerging with age. Together, these changes in synapse structure and function are thought to underlie the cognitive deficits observed in AD.
2. 2 Neural Plasticity
the physiological and behavioral consequences of AD neu- these experiments, it is first necessary to fluorescently
ropathology in order to investigate the fundamental question label dendritic spines and pathological lesions such as
of the underlying anatomical causes of dementia. APP and plaques and tangles. Spines can be imaged with transgenic
APP/PS1 transgenic mice express high levels of amyloid beta expression of fluorophores such as GFP and YFP [26–
(Aβ) and progressively develop many of the pathological 29] or through filling neurons with fluorescent dextrans
phenotypes of AD, including abundant extracellular Aβ [30] or fluorescent proteins expressed in adeno-associated
plaques, synaptic dysfunction and loss, astrocytosis, activa- virus or lentivirus [21, 31]. To label plaque pathology in
tion of microglia, and cognitive deficits [12]. For decades, AD models, the blood-brain barrier-penetrable compounds,
Aβ plaques were thought to cause dementia in AD patients Pittsburghs compound B and methoxy-XO4 (developed by
by physically interrupting normal neural connectivity and William Klunk), have been used in conjunction with in vivo
function. However, the lack of correlation between Aβ multiphoton imaging to observe amyloid plaques and their
plaque load and the degree of cognitive impairment in AD clearance after treatment with immunotherapy [32–35].
patients [4] and the fact that Aβ plaques occupy a negligible Imaging of amyloid plaques together with imaging
fraction (less than 5%) of the neuropil [13–15] in cognitively dendrites and dendritic spines filled with fluorescent proteins
impaired transgenic mice [15] raised the possibility that can be used to assess the effects of pathology on the
fibrillar Aβ in plaques does not contribute significantly to surrounding neuropil (Figure 1). This technique shows that
dementia in AD patients. Instead, soluble Aβ species (i.e., plaques form rapidly, over the course of one day, and
monomeric, oligomeric, and protofibrillary Aβ species that that within one week of plaque formation, surrounding
linger in aqueous solution after high-speed centrifugation) dendrites begin to curve and exhibit dystrophic swellings
seem to be the main culprits of the functional deficits in these [36]. Spine loss around plaques was determined to be due
mice and probably also in initiating disease in AD patients. to a loss of stability of spines in the vicinity of plaques
Mice expressing dementia-associated tau mutations have with more spine elimination than that in control brain,
also been developed to study the contributions of neurofib- reflecting dysfunctional structural plasticity [37]. These
rillary pathology to dementia and the interplay between Aβ structural plasticity changes contribute to functional deficits
and tau [16, 17]. While genetic studies clearly implicate around plaques. In one study, neural circuit function was
amyloid as the initiating factor in AD, the correlation of assessed using a fluorescent reporter of neuronal activation
tangles with neuronal loss in AD brain, together with (the coding sequence of Venus, flanked by short stretches
the lack of neuronal loss and tangle formation in APP of the 5 and 3 untranslated regions from CamKIIα)
transgenic models, and the lack of efficacy with Aβ-directed which gets transported to dendrites and locally translated
therapeutics have contributed to the idea that tau pathology in response to activity resulting in increased fluorescence
is an important contributor to dementia downstream of Aβ in dendrites after neuronal activation. APP/PS1 transgenic
[18]. mice have greatly reduced levels of this reporter in dendritic
This paper will review the work on dendritic spine segments surrounding plaques, and they failed to upregulate
changes and their contribution to functional changes in its expression in response to environmental stimulation,
synapses and behavioral deficits in AD models. It is impor- a phenomenon which was robust in wild-type animals
tant to address these questions because the ability of synapses [38]. Resting intraneuronal calcium levels are also disrupted
and spines to change even in aged brain and the strong around plaques, indicating dysfunction [39].
correlation between synapse loss and cognitive decline in AD From the above studies, it is clear that plaques affect
indicate that enhancing spine plasticity could prevent or even local dendrites and dendritic spines, but the precise bioactive
reverse cognitive deficits associated with neurodegenerative molecule around plaques which induces spine loss was not
disease. clear for many years. The strongest candidate for the synap-
totoxic molecule around plaques arose as soluble oligomeric
Aβ due to work by William Klein, Dennis Selkoe, and other
2. In Vivo Imaging Reveals Dendritic groups who reported that soluble Aβ causes dendritic spine
Spine Loss and Plaque-Associated Structural collapse and impairs synaptic plasticity in culture [40–44],
Plasticity Deficits in AD Models correlates with memory loss in transgenic mice [45, 46],
and impairs memory and synaptic plasticity in vivo [47,
Dendritic spines form the postsynaptic element of the 48]. In further support of the synaptotoxic role of Aβ,
vast majority of excitatory synapses in the cortex and both active and passive immunotherapy to remove Aβ have
hippocampus brain regions important for learning and favorable effects on memory, plaque clearance, and neurite
memory. Changes in spines are thought to be a structural architecture in AD models [33, 49–53]. The first direct
basis for these processes [3]. Loss of dendritic spines similar assessment of whether oligomeric Aβ is present at synapses
to the synapse loss observed in human AD has been reported in the brain came from application of the array tomography
in several mouse models that develop amyloid and tau technique to AD mouse brain tissue. Array tomography,
pathology [13, 19–25]. The use of mouse models for in developed by Micheva et al., overcomes the axial resolution
vivo multiphoton imaging allows longitudinal investigations limitation of confocal microscopy by physically sectioning
to determine the temporal sequence of pathological events tissue into 70 nm ribbons of serial sections which can then be
and to answer “chicken-or-egg” questions such as which used for immunofluorescent analysis to accurately quantify
comes first, spine loss or plaques? In order to perform the contents of small structures such as synapses [54, 55].
3. Neural Plasticity 3
y
x
z
(a) (b)
Figure 1: In vivo multiphoton imaging of plaques (labeled with methoxy X-O4, blue), vasculature (labeled with Texas red dextran, red), and
dendrites (transgenically expressing YFP, green) in mice transgenic for mutant human APP and PS1 crossed with YFP transgenic mice allow
examination of dendritic spine plasticity and loss. Low-resolution three-dimensional image stacks (a) are used to repeatedly find the same
imaging sites. Higher-resolution image stacks (b) are used for spine analysis. Scale bars 100 μm (a) 10 μm (b).
In APP/PS1 mice, this technique shows that oligomeric Aβ is protein PSD95 and disrupting this interaction of tau, and
in fact present at a subset of shrunken excitatory postsynaptic Fyn prevents Aβ toxicity in APP transgenic mice [70].
densities, particularly in a halo of oligomeric Aβ surrounding Similarly, Roberson et al. found that Aβ, tau, and Fyn jointly
the dense cores of plaques [56]. As would be predicted from impair synaptic network function in electrophysiological
the association of dendritic spine changes with physiological studies of APP and Fyn overexpressing mice on a tau null
plasticity [57–59] and the presence of oligomeric Aβ at background [71]. In culture, oligomeric Aβ was found to
shrinking spines, dendritic spines can recover with thera- cause tau mislocalization to dendrites which was associated
peutic interventions aimed at removing oligomeric Aβ or with local calcium elevation and dendritic spine loss [72].
inhibiting calcineurin which is activated downstream of Aβ-
associated increases in intracellular calcium [30, 39, 60–62]. 3. Synaptic Plasticity Is Severely Impaired in
Removing soluble Aβ with the topical application of the 3D6 AD Mouse Models
antibody allows rapid increases in the structural plasticity
of dendritic spines within one hour, before any clearance of It is widely accepted that, in early stages of AD, synaptic
fibrillar Aβ occurs [30]. dysfunction is the cause of dementia [84, 85]. Synaptic plas-
Tau overexpression has also been associated with spine ticity provides a neurophysiological substrate for learning
loss in postmortem studies of human tau transgenic ani- and memory and is, therefore, often used to evaluate the
mals [25]. In rTg4510 mice, pyramidal cells have reduced phenotype of transgenic mice. In APP transgenic AD mouse
spine density compared to wild-type animals, but tangle- models, there are significant alterations in hippocampal
bearing neurons have no more loss than their non-tangle- synaptic transmission and plasticity at excitatory glutamater-
bearing neighbors [25]. Similarly rTg4510 hippocampal gic synapses that sometimes appear in young animals long
circuits are deficient in experience-dependent upregulation before Aβ is deposited in plaques (see Table 1). Most studies
of immediate early genes compared to wild-type mice, but performed before mice reached 6 months of age report
tangle-bearing neurons are not impaired compared to non- intact basal synaptic transmission [75, 78, 81, 83] although
tangle-bearing cells in rTg4510 brain [63]. In vivo and some exceptions were also reported [74, 86]. It should be
array tomography imaging of tangles in rTg4510 mice has noted that the lack of detectable changes in basal synaptic
been developed and is demonstrating similar indications transmission in the majority of studies does not rule out
that soluble tau may be more toxic than fibrillar tau in synaptic dysfunction that has been overcome by functional
terms of axonal transport and neuronal death [64–68]. In compensation. Indeed, evidence of functional compensation
cultured neurons and transgenic mice overexpressing tau, in response to spine loss induced by Aβ has been observed
mislocalization of tau to dendritic spines disrupts synaptic in several models [87–89]. From 6 months on, most of the
function [69]. AD transgenic mice show significant deficits in basal synaptic
Very recent data elegantly link Aβ, tau, and dendritic transmission [75, 78, 79, 81–83, 90]. This age-related
spine loss [70, 71]. Ittner et al. established that tau has a deterioration in synaptic transmission in AD transgenic mice
dendritic function in targeting the Src kinase Fyn to dendritic is unlikely to result from a decreased transmitter release
spines. Fyn phosphorylates NMDA receptor NR2 subunits probability because paired-pulse facilitation (PPF), which
mediating their interaction with the postsynaptic scaffolding correlates inversely with the probability of transmitter release
4. 4 Neural Plasticity
Table 1: Progressive synaptic malfunction AD transgenic mice.
Age Paired-pulse
Model Mutations Basal synaptic transmission Long-term potentiation
(months) facilitation
2-3 Impaired [73]
4–6 Impaired [74] Normal [74]/impaired [73]
Tg2576 APPswe
6–12 Impaired [75] Normal [75]
>12 Normal [76, 77]/Impaired [75] Normal [75]/impaired [76, 77] Normal [4, 6]
<6 Normal [78] Impaired [78] Impaired [78]
PDAPP APP (V717F) 6–12
>12 Impaired [78] Normal [78] Impaired [78]
<6 Normal [79] Impaired [79, 80]
APP/PS1 APPswe/PS1dE9 6–12 Impaired [79, 80] Impaired [79, 80] Normal [80]
>12
1-2 Normal [81] Normal [81] Normal [81]
3–6
3xTg-AD APPSwe, PS1M146V, and tauP301L
6–12 Impaired [81] Impaired [81] Normal [81]
>12
APPswe/lnd/fl and a PS1 transgene <6 Normal [82] Normal [82] Normal [82]
5XFAD carrying double FAD mutations 6–12 Impaired [82, 83] Impaired [82, 83] Normal [82]
(M146L and L286V) >12
[78], remains intact in most of AD transgenic mice, even at with molecular and cellular changes. The implication of
advanced ages [78, 86] (see Table 1). Impairments in long- Aβ in the cognitive decline in AD transgenic mice is no
term potentiation (LTP) were shown both in vitro and in longer controversial. However, there were contrasting reports
vivo, in the CA1 as well as dentate gyrus regions of the regarding the onset of cognitive decline in different AD
hippocampus [76, 91]. Failure of LTP expression is detected models (Table 2). In some studies, deficits in learning and
in AD mice in some cases before 4 months of age [73, 78] but memory were observed at 3 months, implicating soluble
usually appears later [75, 76, 81–83, 86, 92], when Aβ load Aβ assemblies [98, 99], while other studies have shown
is higher. These findings emphasize the fact that extracellular onsets at intermediate ages [76, 98, 100–104] or at advanced
deposition of fibrillar Aβ is not required for the development ages [100, 101, 105, 106], invoking insoluble Aβ plaques.
of severe functional deficits in AD models. This conclusion is Moreover, in the 3XTg-AD mouse model, spatial long-
strengthened by the observation that direct application of Aβ term retention memory deficits were found to correlate
oligomers into the brain prevents LTP [48, 93, 94]. with intraneuronal Aβ at 4 months [81], an age when
Studies of the mechanisms of Aβ-mediated synaptic these transgenic mice do not have Aβ plaques [107]. A
dysfunction converge on the theme of increased postsynaptic similar observation has been shown for 5x FAD mice,
calcium concentrations leading to internalization of NMDA which also accumulate high amounts of intraneuronal Aβ
and AMPA receptors via mechanisms similar to those seen in peptides [108] and present with significant impairment in
long-term depression [40, 42, 95, 96]. Overall, these findings the working memory already at 4-5 months of age [102,
suggest that synaptic dysfunction is an early event in AD 103]. Due to this controversy, the Aβ species responsible
pathogenesis and may play a role in the disease process. for the cognitive decline in these mice was under debate for
many years. Strong evidence for the toxicity of soluble Aβ
came from a study showing that naturally secreted soluble
4. Impaired Cognition in AD Mouse Models Aβ oligomers administrated into the rat’s lateral cerebral
ventricles at picomolar concentrations disrupt the memory
Learning and memory processes are believed to depend of a complex learned behavior [47]. This suggests that soluble
on changes of synaptic transmission in certain areas of Aβ oligomers, rather than Aβ plaques, may be responsible
the brain, including the hippocampus. Most studies done for the cognitive impairment in the absence of Aβ plaques or
with AD transgenic mice assess spatial navigation capability neuronal death.
(e.g., Morris water maze, radial maze, Barnes maze) since Although aged AD mice are impaired at learning several
this memory system depends on the hippocampus and is tasks that depend on the hippocampus, the performance
highly conserved in mammals [97]. The onset of cognitive of these mice on tasks requiring an intact amygdala, such
decline is difficult to define in humans, particularly without as cued-fear conditioning, has been thoroughly established
a reliable biomarker. Thus, the use of transgenic mouse only for Tg2576 mice [112, 119] and aged APP/PS1 mice
models to address this question is particularly useful, since [15]. In these models amygdala-dependent learning is
the early cognitive changes can be identified and correlated severely impaired at advanced ages, implying that neurons of
5. Neural Plasticity 5
Table 2: Progressive cognitive impairments in APP AD transgenic mice.
Age Spatial task Fear conditioning
Model Working memory
(months) Learning Probe test Contextual Cued
Impaired [109]/normal Normal [110]/impaired Impaired
<6 Normal [100, 111] Normal [119]
[98, 100, 110] [98] [74, 109, 112–118]
Normal [101]/impaired Normal [120]/ Normal Impaired
Tg2576 6–12 Normal [122]
[110, 120] impaired [111] [98, 101]/impaired [110] [115, 121]/normal [122]
Normal [112,
Impaired
>12 Impaired [101, 110] Impaired [111] Impaired [112, 115, 117] 119]/impaired
[76, 98, 101, 110]
[119]
Normal
Normal [126, 127]/ Normal [124, 127, 129, [131–133]/impaired
<6 Normal [123–128]
impaired [128] 130]/impaired [80] [79, 117]/enhanced
[127]
APP/PS1 Impaired Normal [105, 127,
Impaired Impaired [79]/normal
6–12 [79, 80, 105, 126– 134]/impaired
[80, 127, 129, 130] [127]
128, 134] [79, 80, 126, 128]
Impaired
>12 Impaired [105, 106] Impaired [124, 129] Impaired [15]
[105, 106, 124, 128, 135]
1-2 Normal [107] Normal [107] Normal [107, 136]
Impaired
3– 6 Impaired [137–139] Normal [136]
3xTg-AD [107, 137, 138]
Impaired
6–12 Impaired [107, 140] Impaired [136, 139, 141] Impaired [139]
[107, 139, 140]
>12 Impaired [142] Impaired [141, 143]
<6 Impaired [108, 144] Normal [102, 108] Normal [82, 145] Normal [144]
5XFAD 6–12 Impaired [144] Impaired [102, 103] Impaired [82, 144, 145]
>12 Impaired [102, 103, 146]
the amygdala, similar to hippocampal neurons, are suscepti- are characterized by a number of specific cognitive deficits,
ble to the toxic effect of Aβ. compatible with AD, which makes them indispensable for
At later stages of the disease, widespread synaptic and testing of novel anti-AD drugs. Finally, the plastic nature of
neuronal death probably contribute greatly to dementia. synapses and their clear involvement in both early and late
These effects are likely mediated by tau downstream of stages of cognitive decline in these AD models highlight the
the initiating amyloid pathology [18]. Reflecting this later importance of synaptic targets for therapeutic approaches.
stage of dementia, tau-expressing mouse lines which undergo
neuronal loss develop behavioral deficits. Interestingly, two
of these mouse lines which have reversible expression of References
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