This powerpoint discusses the role of transition metals and amyloid plaque formation in Alzheimer’s disease (AD) and how metal ion chelators may be employed as therapeutic agents for AD. It describes the disorder, how it progresses and what happens to the brain tissue.
Furthermore, within the presentation I describe a drug which chelates metals including a description about the chemical formulation of these drugs and how the drug can be preventative of AD.
ROLE OF FREE RADICAL IN NEURODEGENERATIVE DISEASE
Oxidative stress in AD??
Oxidative stress occurs when there is an imbalance between t he production and quenching of free radicals from oxygen species. These reactive oxygen species (ROS) play a role in many chronic diseases including mitochondrial diseases, neurodegenerative diseases, renal disease, arteriosclerosis, diabetes , cancer.
The process of aging is also associated with increased oxidative stress. Through pathological redox reactions ROS can denature biomolecules such as proteins, lipids and nucleic acids. This can initiate tissue damage via apoptosis and necrosis.
Oxidative stress plays a central role in the pathogenesis of AD leading to neuronal dysfunction and cell death.
Peripheral markers of oxidative stress are elevated in AD indicating that the damage is not brain-limited.
The increased level of oxidative stress in the AD brain is reflected by
increased protein and DNA oxidation,
Decreased level of cytochrome C oxidase and advanced glycosylation end products.
enhanced lipid peroxidation,
Lipid peroxidation can weaken cell membranes causes ion imbalance and impair metabolism.
Oxidative stress can influence DNA methylation which regulates gene expression.
Internalized beta-amyloid may play a role in this process.
Mitochondrial dysfunction, which is associated with an accumulation of ROS, appears to play a role in the early events of AD pathology.
PROTAC Technology in Tumor Targeted Therapy - Creative BiolabsCreative-Biolabs
Today, we will explore the protac technology applied in tumor-targeted therapy. The following will be presented to you, such as a brief introduction to Protac, the mechanism of action, the advantages and disadvantages of protac as a drug, and the core content: the application of protac technology in tumor therapy. And the last part, the protac solutions provided by Creative Biolabs. If you have any questions about the PROCT development, please email us.
Email: info@creative-biolabs.com
ROLE OF FREE RADICAL IN NEURODEGENERATIVE DISEASE
Oxidative stress in AD??
Oxidative stress occurs when there is an imbalance between t he production and quenching of free radicals from oxygen species. These reactive oxygen species (ROS) play a role in many chronic diseases including mitochondrial diseases, neurodegenerative diseases, renal disease, arteriosclerosis, diabetes , cancer.
The process of aging is also associated with increased oxidative stress. Through pathological redox reactions ROS can denature biomolecules such as proteins, lipids and nucleic acids. This can initiate tissue damage via apoptosis and necrosis.
Oxidative stress plays a central role in the pathogenesis of AD leading to neuronal dysfunction and cell death.
Peripheral markers of oxidative stress are elevated in AD indicating that the damage is not brain-limited.
The increased level of oxidative stress in the AD brain is reflected by
increased protein and DNA oxidation,
Decreased level of cytochrome C oxidase and advanced glycosylation end products.
enhanced lipid peroxidation,
Lipid peroxidation can weaken cell membranes causes ion imbalance and impair metabolism.
Oxidative stress can influence DNA methylation which regulates gene expression.
Internalized beta-amyloid may play a role in this process.
Mitochondrial dysfunction, which is associated with an accumulation of ROS, appears to play a role in the early events of AD pathology.
PROTAC Technology in Tumor Targeted Therapy - Creative BiolabsCreative-Biolabs
Today, we will explore the protac technology applied in tumor-targeted therapy. The following will be presented to you, such as a brief introduction to Protac, the mechanism of action, the advantages and disadvantages of protac as a drug, and the core content: the application of protac technology in tumor therapy. And the last part, the protac solutions provided by Creative Biolabs. If you have any questions about the PROCT development, please email us.
Email: info@creative-biolabs.com
Autophagy the housekeeper in every cellfathi neana
Autophagy is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products.
It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer.
A brief introduction about Pharmacology of free radicals, generation of free radicals, Antioxidants, Free radicals causing disorders such as cancer diabetes, neuro degenerative disorders such as Parkisonism's Disease
Molecular Mechanisms of Neurodegeneration: Neurodegenerative Disorders Webin...QIAGEN
Common molecular mechanisms and pathways leading to neurodegeneration, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease or Multiple Sclerosis, are presented in this slideshow. Learn more about research and therapeutic strategies as well as how these discoveries and tools can be used to facilitate your neurodegeneration research.
Pharmacogenomics is the branch of biochemistry in which study how an individual’s genetic inheritance affects the body response to drug. Pharmacogenomics is the intersection of genetics and pharmaceutical industry.
In this presentation a brief note is given about what is pharmacogenomics. Why different drugs work differently in different people. today pharmacogenomics, future of pharmacogenomics. also describe the future of pharmacogenomics. challenges which have to pharmacogenomics.
here is some information about autophagy, how it happend, when it happend and it's mechanism.
and some information about it's effect on cancer and some disorders.
Reactive Oxygen Species in Signal Transduction and its applicationsMostafa Mohamed
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Applications for Drugs Targeted to Increase ROS in Cancer Treatment
During favorable conditions, the level of reactive spices in the cell is limited to what is required for normal cellular activities. They act as important components of signaling pathways. Plants control some important processes such as defense, hormonal signaling and development by using them as signaling molecules. And An equilibrium is steblished between antioxidant system and ros formation. But when plant feels an external stress like, drought,cold, salt etc. the level of reactive specease increases above the basal level a situation that we call oxidative stress. These reactive molecules during oxidative stress, they react with biomolecules like as carbohydrates, unsaturated lipids, proteins, nucleic acids. Proteins are the most abundant cellular targets of the oxidative species, more than DNA and lipids, making up 68% of the oxidized molecules in the cell. Ros reacts with proteins which results in protein modification called redox PTMs.
Autophagy the housekeeper in every cellfathi neana
Autophagy is a catabolic process involving the degradation of a cell’s own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products.
It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more-essential processes. Autophagy is an evolutionarily conserved mechanism of cellular self-digestion in which proteins and organelles are degraded through delivery to lysosomes. Defects in this process are implicated in numerous human diseases including cancer.
A brief introduction about Pharmacology of free radicals, generation of free radicals, Antioxidants, Free radicals causing disorders such as cancer diabetes, neuro degenerative disorders such as Parkisonism's Disease
Molecular Mechanisms of Neurodegeneration: Neurodegenerative Disorders Webin...QIAGEN
Common molecular mechanisms and pathways leading to neurodegeneration, such as Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease or Multiple Sclerosis, are presented in this slideshow. Learn more about research and therapeutic strategies as well as how these discoveries and tools can be used to facilitate your neurodegeneration research.
Pharmacogenomics is the branch of biochemistry in which study how an individual’s genetic inheritance affects the body response to drug. Pharmacogenomics is the intersection of genetics and pharmaceutical industry.
In this presentation a brief note is given about what is pharmacogenomics. Why different drugs work differently in different people. today pharmacogenomics, future of pharmacogenomics. also describe the future of pharmacogenomics. challenges which have to pharmacogenomics.
here is some information about autophagy, how it happend, when it happend and it's mechanism.
and some information about it's effect on cancer and some disorders.
Reactive Oxygen Species in Signal Transduction and its applicationsMostafa Mohamed
Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling
Applications for Drugs Targeted to Increase ROS in Cancer Treatment
During favorable conditions, the level of reactive spices in the cell is limited to what is required for normal cellular activities. They act as important components of signaling pathways. Plants control some important processes such as defense, hormonal signaling and development by using them as signaling molecules. And An equilibrium is steblished between antioxidant system and ros formation. But when plant feels an external stress like, drought,cold, salt etc. the level of reactive specease increases above the basal level a situation that we call oxidative stress. These reactive molecules during oxidative stress, they react with biomolecules like as carbohydrates, unsaturated lipids, proteins, nucleic acids. Proteins are the most abundant cellular targets of the oxidative species, more than DNA and lipids, making up 68% of the oxidized molecules in the cell. Ros reacts with proteins which results in protein modification called redox PTMs.
Based on Capillary Gate Theory and Tissue Repair Theory, this presentation will explain the recently identified “Stress Repair Mechanism” (SRM) that enables the long-anticipated Universal Theory of Medicine postulated by Hans Selye in 1954. The SRM maintains and repairs vertebrate tissues and accounts for most of the mysterious manifestations of allostasis that remain unexplained by Hypothalamic-Pituitary-Axis (HPA) hormones. SRM activity explains hemodynamic physiology, capillary hemostasis, infarction, Korotkoff sounds, blood pressure, hypertension, diabetes, allostasis, allostatic load, anesthesia, analgesia, atherosclerosis, apoptosis, malignancy, eclampsia, sepsis, Multi-System Organ Failure (MSOF), the surgical stress syndrome, the fight or flight response, and numerous other manifestations of physiology, pathology, and allostasis. SRM function comprises the autonomic nervous system, the vascular endothelium, and the dynamic enzymatic interaction of blood-borne hepatic Factors VII, VIIIC, IX and X that produces thrombin, soluble fibrin and insoluble fibrin, whose combined effects account for all SRM manifestations. The vascular endothelium is a diaphanous neuroendocrine organ that lines all blood vessels and is the sole constituent of capillary walls. It secretes tissue factor into extravascular tissues, and insulates those tissues from the hepatic enzymes, so that tissue disruption exposes tissue factor to the enzymatic interaction and activates tissue repair. The vascular endothelium also releases nitric oxide and von Willebrand Factor into blood in accord with autonomic balance to regulate the enzymatic interaction to govern tissue perfusion and organ function. Therefore, continuously fluctuating combinations of nervous stimuli that affect autonomic balance and forces that disrupt tissues determine SRM activity.
There is increasing evidence that free radical-induced oxidative damage may play a role in the pathogenesis of Alzheimer's disease. Free radicals are reactive oxygen compounds that may attack and damage lipids, proteins, and DNA. The brain is especially sensitive to oxidative damage because of its high content of readily oxidized fatty acids, high use of oxygen, and low levels of antioxidants. Evidence for oxidative damage has been obtained from postmortem brain tissue as well as from living patients with Alzheimer's disease. Antioxidants such as vitamin E show promise that they may help in treating the disease.
definition, properties, types of free radical, neurodegenerative disorder, cardiovascular disease, and cancer due to free radicals, importance of antioxidants and their role.
Neurobiology of Alzheimer’s disease
Role of Acetyl choline
Amyloid-beta-mediated neurodegeneration
Amyloid beta accumulation
Amyloid cascade hypothesis
Microtubule-associated protein tau
Oxidative stress
ROS-mediated neuronal damage
A2 - Unit 4 - Module 2 - OCR - Excretion - All Notes Final Pırıl Erel
Slides specifically for OCR syallbus during A-Levels, this is for A2 - Unit 4 - Module 2 - 1.2.1 - 1.2.8. I have made these for my students and they have found them very useful.
Includes Summary Questions, Further Application questions and key definitions at the end of the slides
Slides aimed for teachers, but can be used as revision slides for students also.
More than welcome to download, good luck with exams!
Analysis in to the Epidemiology and Pathophysiology of Respiratory Syncytial ...Pırıl Erel
Respiratory Syncytial Virus (RSV) places the heaviest clinical burden on paediatric wards in the UK and the US. It is in fact, a global issue with 3.4 million hospitalisations and approximately 66,000 deaths worldwide per annum (Bush et al., 2007) (Lambert et al., 2014). RSV is the leading cause, especially during the winter months, of severe respiratory infections in infants resulting in a rise in hospital admissions where 0.5-1% of infected babies die from respiratory failure. It is also a significant respiratory concern in the elderly population. (Agoti et al., 2014)
RSV has shown to have a willful ability to enter the host resulting in illness both by viral mechanisms and proteins encoded by RSV, dysregulating the synthesis of systemic immune response of the host. Alongside the infiltration of RSV, the heath status and genotype of the host will be a key factor in predetermining disease susceptibility and severity.
It is important to understand RSV has been implicated with further acute and chronic illnesses therefore by considering the epidemiology and pathophysiology of RSV treatment may be implicated during early stages which can influence possible outcomes in the future.
1.2.3 - OCR - A2 - Module 2 - Function of the Liver by Piril ErelPırıl Erel
Slides specifically for OCR syallbus during A-Levels, this is for A2 - Module 2 - The function of the Liver - 1.2.3 - I have made these for my students and they have found them very useful.
Slides aimed for teachers, but can be used as revision slides for students also.
More than welcome to download, good luck with exams!
AQA AS Biology - Unit 1 - Biology and Disease - Chapter 2 (2.1 and 2.4) - Dig...Pırıl Erel
Slides specifically for AQA syallbus during A-Levels, this is for unit 1 - biology of disease - chapter 2 (specifically 2.1 and 2.4) I believe these chapters go hand in hand, I have made these for my students and they have found them very useful.
Slides aimed for teachers, but can be used as revision slides for students also.
More than welcome to download, good luck with exams!
Analysis in to the Epidemiology and Pathophysiology of Respiratory Syncytial ...Pırıl Erel
Respiratory Syncytial Virus (RSV) places the heaviest clinical burden on paediatric wards in the UK and the US. It is in fact, a global issue with 3.4 million hospitalisations and approximately 66,000 deaths worldwide per annum (Bush et al., 2007) (Lambert et al., 2014). RSV is the leading cause, especially during the winter months, of severe respiratory infections in infants resulting in a rise in hospital admissions where 0.5-1% of infected babies die from respiratory failure. It is also a significant respiratory concern in the elderly population. (Agoti et al., 2014)
RSV has shown to have a willful ability to enter the host resulting in illness both by viral mechanisms and proteins encoded by RSV, dysregulating the synthesis of systemic immune response of the host. Alongside the infiltration of RSV, the heath status and genotype of the host will be a key factor in predetermining disease susceptibility and severity.
It is important to understand RSV has been implicated with further acute and chronic illnesses therefore by considering the epidemiology and pathophysiology of RSV treatment may be implicated during early stages which can influence possible outcomes in the future.
How Helicobacter Pylori can cause gastric ulcerations and how this can lead t...Pırıl Erel
Analysis and disccusion of how Helicobacter Pylori (H.pylori) developed genetically and physically as a bacterium to be effective in affecting host cells. It has successfully affected 50% of host cells within the human population. Retrospective research of genomic advances and interactions of H.pylori migration between old and new world.
How much do we really understand about Schizophrenia and to what extent is so...Pırıl Erel
This essay analyses what the mental disorder Schizophrenia (SZ) is, examining in detail medical research such as; symptoms and behaviour of patients, how to identify this mental disorder what type of treatment is available. Furthermore it will explore society’s behaviour towards this disorder and scrutinising the question ‘To what extent are we responsible for the nurture and care of vulnerable individuals?’
The French Revolution, which began in 1789, was a period of radical social and political upheaval in France. It marked the decline of absolute monarchies, the rise of secular and democratic republics, and the eventual rise of Napoleon Bonaparte. This revolutionary period is crucial in understanding the transition from feudalism to modernity in Europe.
For more information, visit-www.vavaclasses.com
Safalta Digital marketing institute in Noida, provide complete applications that encompass a huge range of virtual advertising and marketing additives, which includes search engine optimization, virtual communication advertising, pay-per-click on marketing, content material advertising, internet analytics, and greater. These university courses are designed for students who possess a comprehensive understanding of virtual marketing strategies and attributes.Safalta Digital Marketing Institute in Noida is a first choice for young individuals or students who are looking to start their careers in the field of digital advertising. The institute gives specialized courses designed and certification.
for beginners, providing thorough training in areas such as SEO, digital communication marketing, and PPC training in Noida. After finishing the program, students receive the certifications recognised by top different universitie, setting a strong foundation for a successful career in digital marketing.
Acetabularia Information For Class 9 .docxvaibhavrinwa19
Acetabularia acetabulum is a single-celled green alga that in its vegetative state is morphologically differentiated into a basal rhizoid and an axially elongated stalk, which bears whorls of branching hairs. The single diploid nucleus resides in the rhizoid.
How to Make a Field invisible in Odoo 17Celine George
It is possible to hide or invisible some fields in odoo. Commonly using “invisible” attribute in the field definition to invisible the fields. This slide will show how to make a field invisible in odoo 17.
Embracing GenAI - A Strategic ImperativePeter Windle
Artificial Intelligence (AI) technologies such as Generative AI, Image Generators and Large Language Models have had a dramatic impact on teaching, learning and assessment over the past 18 months. The most immediate threat AI posed was to Academic Integrity with Higher Education Institutes (HEIs) focusing their efforts on combating the use of GenAI in assessment. Guidelines were developed for staff and students, policies put in place too. Innovative educators have forged paths in the use of Generative AI for teaching, learning and assessments leading to pockets of transformation springing up across HEIs, often with little or no top-down guidance, support or direction.
This Gasta posits a strategic approach to integrating AI into HEIs to prepare staff, students and the curriculum for an evolving world and workplace. We will highlight the advantages of working with these technologies beyond the realm of teaching, learning and assessment by considering prompt engineering skills, industry impact, curriculum changes, and the need for staff upskilling. In contrast, not engaging strategically with Generative AI poses risks, including falling behind peers, missed opportunities and failing to ensure our graduates remain employable. The rapid evolution of AI technologies necessitates a proactive and strategic approach if we are to remain relevant.
Introduction to AI for Nonprofits with Tapp NetworkTechSoup
Dive into the world of AI! Experts Jon Hill and Tareq Monaur will guide you through AI's role in enhancing nonprofit websites and basic marketing strategies, making it easy to understand and apply.
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty,
International FDP on Fundamentals of Research in Social Sciences
at Integral University, Lucknow, 06.06.2024
By Dr. Vinod Kumar Kanvaria
Exploiting Artificial Intelligence for Empowering Researchers and Faculty, In...
The Role Of Transition Metals & Reactive Oxygen Species (ROS) In Alzheimer's Disease by Piril Erel
1. The role of Transition Metals &
Reactive Oxygen Species (ROS)
in Alzheimer’s Disease(AD).
By Piril Erel
UoB: 12004723
Piril Erel - UoB: 12004723 1
Normal Alzheimer’s
2. Content Pages:
Piril Erel - UoB: 12004723 2
10.Production Of ROS Induced By Aβ
11.Chelating Properties
12.PBT2 detoxifies Aβ Plaques
13.The Healthy Synapse – a glance into the synaptic cleft
14.Alzheimer’s Disease – a glance into the synaptic cleft
15.PBT2 – a glance into the synaptic cleft
16.Trial Method For PBT2
17.Results From PBT2
18.Conclusion
19.Ending
20.References
1. Aims & Objective
2. What Is Alzheimer’s Disease?
3. Risk Factors Associated With AD
4. Metal Homeostasis In Alzheimer’s Disease
5. Pathophysiology of AD
6. The Role Of Transition Metals
7. Amyloid- β(Aβ) Protein Plaque Formation And
How It Links To Transition Metals
8. Aggregation Of Aβ Is Metal Dependent
9. Interactions Of Transition Metals With Amyloid – β
Protein (AβPP)
3. The main aim of this project is to investigate current research in Alzheimer’s Disease(AD)
including novel ways to treat this illness which currently does not have any known cure.
By doing this assignment I will introduce The Metal Hypothesis for AD and a novel drug called
PBT2 which I will discuss in detail.
Objectives:
Explain ‘The Metal Hypothesis’
Provide an insight in the dysfunctions of an AD-brain relating to the Metal Hypothesis
Describe Reduced Oxygen Species (ROS)
Discuss how the Metal Hypothesis integrates with ROS to cause AD
Detail of how PBT2 could be an effective drug for AD patients.
Aims & Objective
Piril Erel - UoB: 12004723 3
4. Alzheimer’s Disease(AD) is a slow progressive and fatal neurodegenerative disease
which is indicated by memory and cognitive dysfunction. Despite increasing
knowledge of genetics, epidemiology and neuropathology AD is not treatable.
Currently, disease modifying drugs or existing therapies only offer short-term
symptomatic relief.
It affects 800,000 people in the UK alone and 36 million people world wide, (data
from 2010), this number approximately doubles every 20 years, and is estimated to
reach 66 million in 2030 and 115 million in 2050.[1] This pressures scientists to make
finding a long term pharmacotherapy a priority.
What Is Alzheimer’s Disease?
Piril Erel - UoB: 12004723 4
5. Risk Factors:
1. Age:
a. 1/5 people over 65 will get Alzheimer’s Disease
b. Up to 50% over age 85 have AD
2. Family History:
a. Strong genetic component in most cases of AD
3. Other:
a. Gender (female; menopause?)
b. Stroke, Obesity, High Cholesterol
c. Diabetes
Piril Erel - UoB: 12004723 5
Risk Factors Associated With AD
6. The brain is a specialized organ which uses key cellular processes to work efficiently,
these processes require a high concentration of transition metal ions such as zinc(Zn)
and copper(Cu).
Zn2+ & Cu2+ are required in neuronal activity within synapses
Due to the necessity of these metal ions, cells have a sophisticated system to maintain
metal-ion homeostasis.
Breakdown of these mechanisms alter the ionic balance and can result in a disease state
such as AD.
These metal ions are suggested to have two distinct roles in the pathophysiology of AD:
1. Aggregation of Aβ peptide plaques
2. Production of reactive oxygen species induced by Aβ.
Metal Homeostasis In Alzheimer’s
Disease
Piril Erel - UoB: 12004723 6
7. Promotion of Aβ in the
brain, which is collected
over decades due to the
presence of raised Zn2+ &
Cu2+ concentrations.
Sequestration of copper
by Aβ, drives the
generation of reactive
oxygen species.
Excessive aggregates of
Aβ trap essential metals:
Zinc & Copper.
Piril Erel - UoB: 12004723 7
Pathophysiology Of AD
8. Metals are involved in essential biological functions but the
transport and utilization are generally controlled by their
chemistry making them physiologically useful and potentially able
to give rise to pathological miracles.
The levels of transition metals such as Cu, Fe and Zn in a healthy
brain neocortical parenchyma are still maintained at a high
concentration, however within an AD-affected brain these
concentrations are increased with the highest levels found within
amyloid plaque deposits[2].
Kenche et al stated that both the Zn2+ released from the
presynaptic terminals and Cu2+ released from the post-synaptic
terminals, following synapse stimulation, are pre-dominantly in a
‘free’ exchangeable form.
These ions, along with Aβ in the synaptic cleft results in an
inevitable interaction.
The Role Of Transition Metals
Pic – Reference:
Henryk Kozlowski, Marek Luczkowski, Maurizio Remelli, Daniel Valensin. (2012).
Copper, Zinc and iron in neurodegenerative diseases (Alzheimer's, Parkinsons's
and prion diseases). Metal Ion in Neurodegenerative Diseases. 256 (Fig. 3.), p1.
Piril Erel - UoB: 12004723 8
9. Aβ is the main component of deposits found in the regions of the
brain involved with memory, emotions and intellectual function
of patients with AD[3].
Cherny et al, 1999 found that the use of promoting chelation of
metals in postmortem studies have shown that Zn2+ and Cu2+
mediate the precipitation of Aβ deposits in AD-brain tissue.
Studies show that the neuropil and amyloid plaques in AD-brains
have a high concentration of Cu and Zn, however we do not know
whether this is due to:
Abnormal activity of Cu (or Zn) homeostasis which initiates
Amyloid- β plaques.
Amyloid plaques having a high affinity to metal ions.
Amyloid plaques acting as metal sinks absorbing the ions into
their core [4].
Amyloid- β(Aβ) Protein Plaque Formation
And How It Links To Transition Metals
Pic2 - Reference:
AHAF (American Health Assistance Foundation). (). Amyloid
Plaques and Neurofibrillary Tangles.. Available:
http://pakmed.net/academic/age/alz/alz030.htm. Last accessed
14th Apr 2013.
Piril Erel - UoB: 12004723 9
11. Aβ – Copper binding forms oxidative crosslinks between
monomers. The resulting cross-linked species are called
oligomers. Oligomers are very difficult for the brain to
clear and can eventually cause neuron death
Craddock et al, 2012 observed metal dyshomeostasis in
a AD-affected mouse model.
The interaction between Aβ and metals therefore
represents a mechanism of therapeutic intervention
that could both normalize metal homeostasis and
reduce the levels of toxic Aβ oligomers in the brain. *5+
Furthermore, Copper binding to A also generates ROS,
this binding causes a detrimental release of ROS.
Piril Erel - UoB: 12004723 11
Interactions Of Transition Metals
With Amyloid - β Protein (AβPP)
12. The brain needs oxygen in order to synthesize the large quantities of ATP required.
This accounts for 20% of the body’s total basal oxygen consumption therefore generates high levels of reactive oxygen
species (ROS).
Exposure to ROS damages neurons in the brain.
Oxidative stress plays an important role in initiating AD through provoking cell signaling pathways. [4]
It represents an imbalance between the amount of ROS being produced and the ability of the body to detect and remove
these toxic substances.
This is due to cellular antioxidant defense mechanisms becoming overwhelmed by ROS causing macromolecular damage. ROS
may also result in harmful effects such as;
Damage of DNA.
Oxidation of polyunsaturated fatty acids.
Oxidation of amino acids in proteins.
Oxidatively inactivation of specific enzymes. [6]
Production Of Reactive Oxygen
Species Induced By Aβ
Piril Erel - UoB: 12004723 12
13. In order for a drug to be used as a potential treatment for brain
disorders, it must possess certain characteristics which enable it to
pass the blood brain barrier(BBB) such as:
Low molecular weight
Poorly charged or not charged at all
Stable
Selectivity of certain metal ions
Low toxicity
Minimum side effects.[7]
Chelating Properties
Piril Erel - UoB: 12004723 13
14. This recently discovered treatment shows rapid improvement in
cognition in mouse models of AD.
A Copper/Zinc Ionophore – it competes for metals but also
redistributes metals back into the cell as it transports ions across
the lipid bilayer.
PBT2 aids the clearance of Aβ aggregates in the brain by targeting
zinc and copper ions effectively it detoxifies the Aβ plaques.
PBT2 has a greater affinity for metal compared to Aβ’s affinity to
metal:
Aβ affinity for Zn is - Kd = 10-9
PBT2 affinity for Zn is - Kd =10-13
Metals are promiscuous, they can jump and bind to which ever is
stronger, so if a metal is bound to an Aβ plaque and PBT2 is present,
due to the 104x greater force, the metal will dissociate and bind to
the drug.
PBT2 provides a mechanism which shuttles metals away from Aβ
PBT2 detoxifies A plaques
Piril Erel - UoB: 12004723 14
15. Zn2+ is exocytosed into the synaptic cleft in
concentrations of around 300 μM
Cu2+ is released post-synaptically following
activation of NMDA with Cu2+
concentrations around 15 μM in the
synaptic cleft.
Once cleavage of APP takes place, Aβ is
released into the synaptic cleft and it aids
lowering of zinc concentration by acting as
a sponge.
Aβ is further degraded by enzymes into
smaller monomers.[8]
The Healthy Synapse – a glance into
the synaptic cleft
Piril Erel - UoB: 12004723 15
16. The decrease in ATP leads to a reduction
metal reuptake, causing the average
concentration of metals to rise over time.
Cu & Zn react with Aβ forming Aβ
oligomers and then, crucially, to Aβ
amyloid plaques
Aβ can bind up to 2.5 moles of metal ions
however the more metals it is bound to,
the more aggregated it becomes
Aβ oligomers are resistant to degradation.
Alzheimer’s Disease – a glance into
the synaptic cleft
Piril Erel - UoB: 12004723 16
17. PBT2:
PBT2 taken orally crosses the blood brain barrier
and can be detected in the synaptic cleft.
PBT2 has a high affinity for metals
Chelation by PBT2 allows Zu & Cu to be removed
from Aβ
The advantage of PBT2 lies in the ionophoric
properties of the drug
Concentrations of the metal ions are reduced to
normal
Thus diverted from binding to Aβ,
This reduces precipitation, reduces covalent Aβ
oligomer formation and reduces toxic redox activity.
PBT2 – a glance into the synaptic
cleft
Piril Erel - UoB: 12004723 17
18. Objectives For Phase IIa:
To test the safety and efficacy of PBT2 in patients with mild AD.
To monitor any changes in cognition after administration of PBT2 using
the Neuro-psychological Test Battery (NTB) which measures Executive
Function(EF).
PBT2 has undergone a 12 week Phase II trial in which the drug was orally
administered daily to 78 patients with mild AD who where randomly
allocated into either one of the 3 groups below:
Placebo
50mg and
250mg
It was a double-blind, randomized, placebo-controlled trial
Trial Method For PBT2
Piril Erel - UoB: 12004723 18
19. Patients with a 250mg dose of PBT2 daily showed a significant increase in EF scores compared to the
placebo group.
250mg dose of PBT2 also showed a significant decrease in Aβ protein plaques.*9+
This shows promising results for PBT2 as a treatment drug for Alzheimer’s Disease. Phase IIb clinical
trials is currently underway this time scientists are evaluating the effect of PBT2 on:
Safety and tolerability
Brain metabolic activity
Brain volumes
Cognition
Functional abilities[10]
Results
Piril Erel - UoB: 12004723 19
20. Through thorough research into this area, current drug trials target memory
deficit in early – moderate Alzheimer’s
However it is questionable whether this is too late.
Consideration of executive function and early treatment of AD; a cure may be
possible or at least consequences are more reversible.
PBT2 not only detoxifies the harmful Aβ plaques but also re-establishes
homeostasis of metals at a stage where neuronal death hasn’t yet occurred.
Clinical trials for PBT2 Phase IIb will hopefully provide promising results for
curing AD.
Conclusion
Piril Erel - UoB: 12004723 20
21. Thank You For Listening & Watching,
Piril Erel
12004723
Piril Erel - UoB: 12004723 21
22. 1. Nicole L Batsch, Mary S Mittelman. (2012). Overcoming The Stigma Of Dementia. Available:
www.alz.co.uk/research/WorldAlzheimerReport2012.pdf. Last accessed 2th Apr 2013.
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Piril Erel - UoB: 12004723 22
References
Editor's Notes
Hi, my name is Piril Erel. I am in my first year Mpharm course. My SSA title is – The role of transition metals and reactive oxygen species(ROS) in AD. I decided to do my presentation in an area, in which, I wanted to work on a subject that was not yet mainstream and kind of out of the box. I got into Alzheimer’s Disease when I was working on Schizophrenia in A-Levels as a extended project and found it very interesting and intriguing information on AD too.
I will talk about the role of metals a s platform of pathophysiology for AD and other neurodegenerative disease My talk will focus on the metal hypothesis and a drug called PBT2 for AD and I will begin with an introduction to AD, quickly moving onto the Metal Hypothesis – role of transition metals.
So the objectives to my presentation are:Explaining the metal hypothesisProviding an insight in the dysfunction of an AD brain relating to the Metal HypothesisDescribing Reactive Oxygen Species (ROS)Discussing how the metal hypothesis integrates with ROS to cause ADDetails of how PBT2 could be an effective drug for AD patients
AD is a slow progressive and fatal neurodegenerative disease indicated by memory and cognitive dysfunction. Although there is an ever increasing knowledge in many medical areas, there still has not yet been a cure for AD. Current treatments are only temporary and try relieving symptoms not the actual underlying illness itself. Some figures for AD:Currently it affects eight hundred thousand in the UK alone. 36 million world wide. This figure is estimated to double every 20 years. Estimated to be 60 million in 2030 and 115 million in 2050. These figures compel researchers and scientists to find a cure as soon as possible.
AD is the most common form of dementia in the elderly, 1/5 people living today over the age of 65 will get AD if we live long enough and upto 50% over the age of 85 have AD. After Age the second greatest risk factor is family history and there is a very strong genetic component in this disease.Other risk factors include gender, females get it more then males and there is some though into whether menopause leads to some energy deprivation and the brain could be a risk factor. Most metabolic issues, obesity high cholesterol, stroke, diabetes. If you look at changes in selected causes of death 2000-2008 you can see that most of these diseases have a decreasing incidence rate apart from AD. Alzheimer’s is going up dramatically as there are no AD survivors as we do not have any drugs to stop this disease.
The brain is a specialized organ which has ‘special activities’ if you think about it, these activities require a high concentration of metal ions such as Zn and Cu. These metals are essential in neuronal activity, within synapses, due to this cells have a system which maintain metal-ion homeostasis. The interruption of these mechanisms alter the ionic balance and result in AD. Metal Ions have 2 roles:Aggregation of AB peptide plaquesProduction of ROS induced by AB
So what is the Metal Hypothesis? Essentially shows that zinc and copper are necessary for the aggregation of A-beta, now what will happen is that, when copper binds to a-beta you will also get a ROS being generated so you actually get a detrimental release of free radicals by the interaction of copper and a beta. But one of the points that we don’t consider is that when we get the excessive aggregates in the brain, the brain has a real tough time getting rid of these. As these aggregates accumulate, the excess a-beta actual trap these metals so zinc and copper no longer because bio-available
Transportation and utilization of anything within the body is maintained by their chemistry, making them physiologically useful and potentially able to give rise to pathological miracles. The concentrations within a health brain of metal ions are high however in AD these are increased even more and highest especially in amyloid plaque deposits. Zn released from the presynaptic terminal and Cu from the postsynaptic terminal are in free exchangeable form, when Abeta is within the synaptic cleft this results in a interaction.
A-beta is found in regions in the brain which govern memory, emotions and intellectual function of patients with AD. Studies have shown that Zn & Cu mediate the precipitation of AB deposits in AD-brain tissue, as a-beta plaques have a high concentration of Cu and Zn within however the three problems scientists has is that we do not know whether the increase in concentration is due to:Abnormal activity of Cu (or Zn) homeostasis which initiates Amyloid- β plaques.Amyloid plaques having a high affinity to metal ions.Amyloid plaques acting as metal sinks absorbing the ions into their core
In a diagram model: Monomers are basically neutral, but Zn & Cu then drive the formation of oligomers, these in excess cause synaptic dysfunction the lodge of Protofibril can then cause membrane disruption then a full blown B-amyloid fibril can cause inflammation and also as neurons start to die here, the neuronal debris will also drive inflammation.
AB and Cu binding forms oxidative crosslinks between monomers, these are then called oligomers. Oligomers are very difficult for the brain to clear and can eventually cause neuron death.The Image shows:Zn imaging in a mouse brain, it is a heat map so red is more and blue is less. Bottom is the AD mouse showing the entire cortex where Zn is bound to a-beta. This interaction between A-beta and metals gives a pathway which could be used as a therapeutic intervention which normalizes metal homeostasis and reduce levels of toxic A-beta oligomers in the brain. Cu binding to A-beta also generates ROS causing a detrimental release of free radicals.
Oxygen is require in the brain to maintain the synthesis of ATP, the brain accounts for 20% oxygen so has a high level of reactive oxygen species (ROS) generated. These exposures to free radicals damage neurons in the brain. Oxidative Stress is the imbalance between the amount of ROS being produced and the ability of the body to detect and remove these toxic substances, this happens because ROS overwhelms cellular antioxidant defense mechanisms causing macromolecular damage such as:Damage of DNAOxidation of polyunsaturated fatty acidsOxidation of amino acids in proteinsOxidatively inactivation of specific enzymes.
A drug must posses certain characteristics to be able to pass the blood brain barrier such as:Low molecular weightPoorly charged or not charged at allStableSelectivity of certain metal ions as we do not want a depletion of metal ions in wholeLow toxicityMinimum side effectsTherefore, scientists have found a newly developed drug called PBT2 which possess most of these characteristics.
So how do we fix this? PBT2 has firstly shown rapid improvement in cognition in mouse models in AD. The idea was that PBT2 would prevent the interactions of A-beta with the metals. It is a copper/zinc ionophore so essentially it competes for metals but also redistributes metals back into the cell as it transports ions across the lipid bilayer. It’s aim is to clear A-beta aggregates in the brain by targeting zinc and copper ions, effectively detoxifying the AB plaques. This type of drug has an affinity for the metal that is strong than a-beta. Metals are promiscuous, they will bind to which ever is stronger, the 10-4x greater force attracts metals to PBT2 more and how PBT2 redistributes metals back into the cell is due to an enzyme within the cell called SOD1 which has an even more stronger affinity to metals compared to a-beta and PBT2, so metals will then again leave PBT2 and bind to SOD1, further more being released back into the cell. Essentially PBT2 is like a bus transporting passengers, in our case metal ions from one place to another. After 2nd bullet point – therefore preventing the interaction of AB + ZN/CU
In an healthy synapse as we have discussed before, zinc is released pre-synaptically at around concentrations of 300um and copper is released post-synaptically at around concentrations of 15um both into the synaptic cleft.. A-beta is released into the synaptic cleft and it will aid in lowering the concentrations of the metal ions by acting as a sponge then A-beta is degraded into small monomer units by enzymes
However, in an AD synapse the decrease in ATP leads to a reduction of metal reuptake, causing the average concentration of metals to rise over time. This is why AD is a slowly progressive fatal neurodegenerative disease. As shown in my previous diagram, metal ions will react with A-beta forming oligomers then crucially to amyloid plaques. The higher the concentration of metals the more stronger and resistant it will be to degradation.
Now how PBT2 interacts within this synapse is again the fact that it has a high affinity for metals so chelates metals allowing copper and zinc to be removed from a-beta, the advantage lies in the chemical properties of PBT2, the ionophoric properties of the drug. PBT2 reduces these concentrations of the metal ions to normal so avoiding the binding between A-beta and the metals, furthermore decreasing precipitation and oligomers and toxic a-beta amyloid plaque forming.
The trail method for PBT2 was conducted by Prana Biotechnology who is the leading researchers in PBT2, their objective was to test the safety and efficacy of PBT2 in patients with mild AD. They also wanted to see changes in cognition after administration of PBT2 using the Neuro-psychological test battery which measures executive function. Executive function loss appears as: depression, apathy and personality changes. A 12-week trial was taken place where PBT2 was administered to 78 patients with mild AD in either one of the three doses:Placebo 50mg 250mg It was a double-blind, randomized, placebo-controlled trial.
250mg dose in patients showed a significant increase in EF scores compared to placebo group. Also showed a significant decrease in a-beta protein plaques. This shows promising results for PBT2 as a therapeutic intervention to cure Alzheimer’s Disease. Phase Iib clinical trials are currently being tested where they’re evaluting the effect of PBT2 on many different aspects.
Finally, through thorough research into this area, current drug trials target memory deficit in early-moderate Alzheimer's however it is questionable whether this is too little too late and whether it is enough as the rising wave is coming over the next couple of years. The aim is to hit Alzheimer’s disease as early as possible, even though no cognitive symptoms pathology is starting and you are on your way maybe 15 years on average before there is any cognitive changes. This may establish a possible cure or at least the consequences will be more reversible at this stage where neuronal death has not yet occurred. The advantage of PBT2 is that it not only removes the toxic a-beta plaques but it also re-establishes homeostasis of metals. Clinical trials for PBT2 will hopefully provide promising result for curing AD.