Alzheimer's disease

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  • Although amyloid plaques or senile plaques may be classified further according to their composition, all contain forms of β-amyloid protein (Aβ). Aβ is a 39- to 42-amino acid peptide that is formed by the proteolytic cleavage of β-amyloid precursor protein (APP) and is found in extracellular deposits throughout the central nervous system (CNS). 9   Aβ is believed to interfere with neuronal activity because of its stimulatory effect on production of free radicals, resulting in oxidative stress and neuronal cell death. In AD, the amyloid deposits are largely spherical, reaching up to 200 μm in diameter, and are prevalent throughout the cortex and hippocampus of brains from affected individuals. Neurofibrillary tangles are paired helical filaments composed of tau protein, which in normal cells is essential for axonal growth and development. However, when hyperphosphorylated, the tau protein forms tangles that are deposited within neurons located in the hippocampus and medial temporal lobe, the parietotemporal region, and the frontal association cortices, leading to cell death.
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  • The biggest risk factor for Alzheimer's disease is increased age. The likelihood of developing Alzheimer's disease After age 65, and rises sharply after age 75 Genetics==== Family history of AD Sex=====Women are more likely to develop AD than men Having Down syndrome
  • Proteolytic processing of amyloid precursor protein (APP) by the secretases. APP is a type-I transmembrane glycoprotein. The majority of APP is processed in the nonamyloidogenic pathway (thick arrow); APP is first cleaved by a-secretase within the amyloid-b peptide (Ab) domain (darker shaded region), leading to APPsa secretion and precluding Ab generation. Membrane-anchored a-carboxy terminal fragment (CTF) is then cleaved by g-secretase within the membrane, releasing the p3 peptide and APP intracellular domain (AICD). Alternatively, amyloidogenesis (thin arrow) takes place when APP is first cleaved by b-secretase, producing APPsb. Ab and AICD are generated upon cleavage by g-secretase of the b-CTF fragment retained in the membrane. Scissors indicate the cleavage sites of a-, b- and g–secretase.
  • The neocortex is part of the cerebral cortex . It is involved in higher functions such as sensory perception , generation of motor commands , spatial reasoning, conscious thought and language .
  • Beta-amyloid (Ab) immunotherapy strategies. Immunotherapy can be achieved through either active immunization with full length Ab or an Ab immunoconjugate, or passive administration of monoclonal anti-Ab antibodies. After active immunization with Ab1–42, the peptide is processed by antigen-presenting cells and Ab fragments are presented to T cells. Subsequently, various B-cells that can recognize epitopes on Ab1–42 are engaged, proliferate and produce polyclonal anti-Ab antibodies. The second type of active immunization approach involves the administration of small fragments of Ab conjugated to an unrelated carrier protein. The immunological response after immunization of an Ab peptide-carrier protein conjugate is similar to the first strategy, with the exception that the T cells are stimulated by the carrier protein rather than the Ab fragment (which lacks T-cell epitopes). The third strategy involves direct administration of monoclonal antibodies directed against Ab and, as such, does not require any type of immunological response from the host.
  • Aging: synapse loss
  • Figure 4 . Oxidative Stress and Mitochondrial Failure.A [beta]-amyloid peptide (A[beta])-centric scheme depicts production of reactive oxygen species (ROS) and reactive nitrogen species (RNS). Their peroxidative attack on cell and organelle membrane lipids yields the mitochondrial toxins hydroxynonenal (HNE) and malondialdehyde. Oxidative damage to membrane-bound, ion-specific ATPases and stimulation of calcium (Ca2+) entry mechanisms - for example, glutamate (N-methyl-d-aspartate [NMDA]) receptors (NMDAr), membrane-attack complex (MAC) of complement, and ion-selective amyloid pore formation - cause cytosolic and mitochondrial Ca2+ overload. Cellular A[beta] directly attacks electron transport complex IV (cytochrome c oxidase) and key Krebs-cycle enzymes ([alpha]-ketoglutarate and pyruvate dehydrogenase) and damages mitochondrial DNA (mtDNA), leading to fragmentation. Lipid peroxidation products also promote tau phosphorylation and aggregation, which in turn inhibit complex I. Exaggerated amounts of ROS and RNS are generated at complexes I and III. As the mitochondrial membrane potential (MPP) collapses and permeability-transition pores ([psi]m) open, caspases are activated. A[beta] also induces the stress-activated protein kinases p38 and c-jun N-terminal kinase (JNK), as well as p53, which are further linked with apoptosis. Substrate deficiencies, notably NADH and glucose, combine with electron transport uncoupling to further diminish ATP production. Alcohol dehydrogenase was recently identified as the mitochondrial-binding target for A[beta]. Endoplasmic reticulum contributions are shown. GLUT1, 4 denotes glucose transporter 1, 4.
  • Long-term potentiation involved in memory
  • However, there’s no single linear chain of events and matters are complicating
  • Alzheimer's disease

    1. 1. Alzheimer’s Disease
    2. 2. <ul><li>What’s Alzheimer’s Disease(AD)? </li></ul><ul><li>Signs/Symptoms </li></ul><ul><li>Stage of progression </li></ul><ul><li>Risk factors </li></ul><ul><li>Pathology </li></ul><ul><li>Ethiology </li></ul><ul><ul><li>Beta-amyloid </li></ul></ul><ul><ul><li>Tau </li></ul></ul>Outline
    3. 3. What’s Alzheimer’s Disease(AD)? <ul><li>AD is an illness of the brain. It causes large numbers of nerve cells in the brain to die. </li></ul><ul><li>AD is a progressive, irreversible brain disease that destroys memory and thinking skills. </li></ul><ul><li>Most common cause of dementia in adults </li></ul>
    4. 4. Pathology <ul><li>Amyloid plaques, </li></ul><ul><li>Neurofibrillary tangles </li></ul><ul><li>Neuron and Synapse loss </li></ul><ul><li>Neuronal cell death </li></ul>Amyloid plaque NFTs
    5. 5. Sign and Symptom <ul><li>Memory loss </li></ul><ul><li>Difficulty performing familiar tasks </li></ul><ul><li>Problems with language </li></ul><ul><li>Disorientation to time and place </li></ul><ul><li>Poor or decreased judgment </li></ul><ul><li>Problems with abstract thinking </li></ul><ul><li>Misplacing things </li></ul><ul><li>Changes in mood or behavior </li></ul><ul><li>Changes in personality </li></ul><ul><li>Loss of initiative </li></ul>
    6. 6. Stage of progression <ul><li>Stage 1 (Mild) </li></ul><ul><ul><li>2 to 4 years </li></ul></ul><ul><ul><li>Less energetic and spontaneous </li></ul></ul><ul><ul><li>Ex. of behaviors </li></ul></ul><ul><ul><li>Getting lost </li></ul></ul><ul><ul><li>Repetitive questions and conversations </li></ul></ul><ul><ul><li>Losing things or misplacing them in odd places </li></ul></ul><ul><ul><li>Noticeable changes in personality or mood </li></ul></ul>
    7. 7. Stage of progression (Con.) <ul><li>Stage 2 (Moderate): </li></ul><ul><ul><li>2 to 10 years </li></ul></ul><ul><ul><li>Clearly disable </li></ul></ul><ul><ul><li>Forget recent events and their personal history </li></ul></ul><ul><ul><li>More disoriented and disconnected from reality </li></ul></ul><ul><ul><li>Speech problems arise and understanding </li></ul></ul><ul><ul><li>Reading and writing are more difficult </li></ul></ul>
    8. 8. <ul><li>Stage 3 (Severe):   </li></ul><ul><ul><li>1 to 3 years during final stage </li></ul></ul><ul><ul><li>lose the ability to feed themselves, speak, recognize people and control bodily functions </li></ul></ul><ul><ul><li>Their memory worsens and may become almost non-existent. They will sleep often and grunting or moaning can be common. </li></ul></ul>
    9. 9. Risk factors <ul><li>Age </li></ul><ul><ul><li>After age 65, and rises sharply after age 75 </li></ul></ul><ul><li>Genetics </li></ul><ul><ul><li>Family history of AD </li></ul></ul><ul><li>Sex </li></ul><ul><ul><li>Women > Men </li></ul></ul><ul><li>Having Down syndrome </li></ul>
    10. 10. <ul><li>Cell damage </li></ul><ul><li>Cerebral cortex </li></ul><ul><li>Hippocampus  </li></ul><ul><li>Long-term memory/ Short-term memory </li></ul><ul><li>Neurotransmitter deficits: </li></ul><ul><li>NE: depression </li></ul><ul><li>5-HT 3 : Depression/Anxiety </li></ul><ul><li>ACh: Memory and Cognition loss </li></ul>http://www.memorylossonline.com/glossary/hippocampus.html
    11. 11. β -amyloid (A β ) <ul><li>A β peptides 36-43 amino acids </li></ul><ul><li>Prevalence of A β peptides : A β 40 , A β 42 </li></ul><ul><li>Amyloid hypothesis : A β monomer Soluble oligomers (2-6 peptides) Amyloid plaques (insoluble fibers) Alzheimer’s disease </li></ul><ul><ul><li>1. Imbalance between production and clearance </li></ul></ul><ul><ul><li>2. Aggregation of peptides Accumulation of A β </li></ul></ul>
    12. 12. β -amyloid production APP : amyloid precursor protein (type-1 transmembrane glycoprotein) BACE-1 : beta-site amyloid precursor protein-cleaving enzyme 1 β -Secretase sAPP : large amyloid precursor protein C83, C99 : 83, 99-residue carboxyl-terminal fragment AICD : amyloid intracellular domain
    13. 13. Aggregation & accumulation of A β <ul><li>A β monomer </li></ul><ul><li>Soluble oligomers </li></ul><ul><li>A β 40 > A β 42 , 2-6 peptides </li></ul><ul><li>The most neurotoxic : dimers & trimers toxic to synapses </li></ul><ul><li>Amyloid plaques or insoluble fibers in neocortex ( Neocortex sensory perception, generation of motor commands, spatial reasoning, and language) </li></ul><ul><li>Pathological features of Alzheimer’s disease (as well as NFT in medial temporal-lobe) </li></ul>
    14. 14. Pathological features of Alzheimer’s disease
    15. 15. Clinical trials of therapeutic management <ul><li>ɣ-secretase inhibitor (LY450139) </li></ul><ul><li>Vaccination </li></ul><ul><ul><li>Phase 2a trial (NCT00021723) : encephalitis and no cognitive </li></ul></ul><ul><ul><li>Phase 2 trial (passive immunization of NCT00112073) : vasogenic cerebral edema in some patients </li></ul></ul><ul><ul><li>Phase 3 trial (NCT00574132 & NCT0088662) </li></ul></ul>
    16. 16. Vaccination Dale Schenk, Michael Hagen, Peter Seubert. Current progress in beta-amyloid immunotherapy. Current Opinion in Immunology , Volume 16, Issue 5 , October 2004 , Pages 599-606
    17. 17. <ul><li>Proteases neprilysin : a membrane-anchored zinc endopeptidase Degradation of A β monomers & oligomers </li></ul><ul><li>Insulin-degrading enzyme : a thiol metalloendopeptidase Degradation of monomer </li></ul><ul><li>Overexpression Prevent plaque formation </li></ul>
    18. 18. [ Tau & Neurofibrillary tangles ]
    19. 19. Axonal transport http://www.mpih-frankfurt.mpg.de/global/Nc/view.htm http://www.colorado.edu/intphys/Class/IPHY3430-200/002cellular.htm
    20. 20. Structural organization of microtubule http://manual.blueprint.org/Home/glossary-of-terms/mechano-glossary--m/mechano-glossary-microtubules
    21. 21. Tau protein <ul><li>Stabilization and assembly of microtubule </li></ul><ul><li>Vesicles transport </li></ul><ul><li>Phosphorylation dependent </li></ul><ul><li>Phosphotau and total Tau in CSF as predicting markers </li></ul>http://www.gate2biotech.com/early-testing-for-alzheimers-disease /
    22. 22. Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. Jan 28;362(4):329-44.
    23. 23. What accelerate Tau accumulation ? <ul><li>Oxidative stress </li></ul><ul><li>Impaired protein-folding function </li></ul><ul><li>Deficient proteasome-mediated proteins clearance </li></ul>
    24. 24. http://missinglink.ucsf.edu/lm/ids_104_neurodegenerative/Case1/Case1Micro2.htm Neurofibrillary tangles
    25. 25. Approaches for therapeutic agents <ul><li>Inhibitors of Tau oxidation and aggregation </li></ul><ul><li>Methylene blue, NCT00568776 </li></ul><ul><li>“ Under way ” </li></ul><ul><li>Polyphenolic agent </li></ul><ul><li>Grape seeds extracts: </li></ul><ul><li>Resveratrol  Aging-suppressor gene </li></ul>
    26. 26. The Synapse in Alzheimer’s Disease
    27. 27. <ul><li>Alzheimer’s disease is primarily disorder of synaptic failure. </li></ul><ul><li>Synaptic failure </li></ul><ul><ul><li>decrease in number </li></ul></ul><ul><ul><li>functional deficit </li></ul></ul>Synaptic failure
    28. 29. Depletion of Neurotrophin Neurotrophins are a family of proteins that induce the survival, development and function of neurons. learning memory behavior
    29. 30. Neurotrophin Types of Neurotrophin <ul><li>Nerve growth factor (NGF) </li></ul>2. Brain-derived neurotrophic factor (BDNF) 3. Novel Neurotrophin-1 (NNT-1) 4. Neurotrophin-3 (NT-3) 5. Neurotrophin-4 (NT-4)
    30. 32. Depletion of neurotrophin
    31. 33. Depletion of neurotransmitter <ul><li>“ Cholinergic hypothesis” </li></ul><ul><li>Loss of cholinergic function in the CNS contributes significantly to the cognitive decline associated with advanced age and AD </li></ul>Building up of  - Amyloid and tua Deficiency of cholinergic projection Alzheimer’s disease
    32. 34. Depletion of neurotransmitter <ul><li>Evident </li></ul><ul><li>↓ Presynaptic α 7-nicotinic Ach receptor (nACh-R) </li></ul><ul><li>¥ A β bind to α 7-nACh-R impair its signaling and the release of Ach. </li></ul><ul><li>↓ Muscarinic ACh receptor </li></ul><ul><li>¥ Stimulate postsynaptic M1 ACh-R </li></ul><ul><li>-> activate PKC favoring processing of amyloid precursor protein that does not yield amyloid. </li></ul><ul><li>Activation of nACh-R or M1-R limited tau phosphorylation </li></ul>
    33. 35. Depletion of neurotransmitter <ul><li>Cholinesterase inhibitor improve neurotransmission but it loss efficacy over time. </li></ul><ul><li>M1 agonist showed improvement in cognition and reduced A β levels in the cerebrospinal fluid. </li></ul><ul><li>(but this agent are toxic) </li></ul>
    34. 36. Synaptic Dysfunction in Alzheimer’s Disease
    35. 37. Mitochondrial Dysfunction in Alzheimer’s Disease
    36. 38. Mitochondrial Dysfunction <ul><li> -amyloid (A  ) is potent mitochondrial poison </li></ul><ul><li>A  inhibits key mt. enzyme  esp. Cyt. c oxidase </li></ul><ul><li>Impairment of electron transport, ATP production, oxygen consumption and mt. membrane potential </li></ul><ul><li>Increase in mt. superoxide (O 2 - ) radical formation  H 2 O 2  oxidative stress, cyt. C release and apoptosis </li></ul>Cyt. C oxidase http :// pharmrev . aspetjournals . org / content / 54/1/101 / F1 . large . jpg
    37. 39. Mitochondrial Dysfunction <ul><li>ROS & RON interact with lipid mb, mb proteins </li></ul><ul><li>Lead to mitochondrial mb potential (MMP) collapses </li></ul><ul><li>Lead to opening of mitochondrial permea - bility transition pore (form when mitochodrial get damaged)  apoptosis </li></ul><ul><li>Antihistamine agent dimebolin  improve cognition and behavior in patients with mild to modest </li></ul><ul><li>Act on NMDA & mt. pore </li></ul>Promote tau phosphorylation TCA cycle Accumulation of mtDNA mutation Stress-activated p38 and JNK Toxic aldehyde disturbs glu transportation New England Journal of Medicine. 362(4):329-344, January 28, 2010.
    38. 40. Mitochondrial Dysfunction Oxidative Stress <ul><li>Dysfunctional mt. release oxidizing free radicals  oxidative stress </li></ul><ul><li>Experimental model show oxidative damage markers occur prior to pathological changes </li></ul><ul><li>A   generator of ROS and NOS  oxidative stress </li></ul><ul><li>RAGE (receptor for advanced glycation end products)  mediate A  ’s pro-oxidant effects on neuron, microglial & cerebrovacular cells </li></ul>
    39. 41. Mitochondrial Dysfunction Oxidative Stress Amany Mohamed , et. al., Int J Alzheimers Dis . 2011 , 127984. A  can be translocated to the cell via interacting with RAGE
    40. 42. Mitochondrial Dysfunction Oxidative Stress A  can be translocated to mt via TOM Inhibit cyt. c oxidase  lead to ROS and oxidative stress Renato X. Santos , et. al., Int J Clin Exp Pathol 2010;3(5):570-581
    41. 43. Mitochondrial Dysfunction Oxidative Stress <ul><li>Elevated levels of free divalent transition metal (Fe, Cu and Zn) and Aluminum related with ROS damage and neurodegeneration </li></ul><ul><li>Seek for therapeutic approach to deal with divalent metals </li></ul><ul><li>So far, safe compound derived from clioquinol (PBT2) – show some efficacy </li></ul>
    42. 44. Mitochondrial Dysfunction Oxidative Stress http :// clinicaltrials . gov /
    43. 45. Mitochondrial Dysfunction Insulin Signaling Pathway <ul><li>Observation of subgroups of AD </li></ul><ul><ul><ul><li>advanced AD have high fasting insulin levels & low rates of glucose disposal </li></ul></ul></ul><ul><ul><ul><li>Levels of insulin receptors, GLU-transport proteins and other insulin-pathway components in brain are reduced in some studies with AD </li></ul></ul></ul><ul><li>Resistance to insulin signaling  energy deficiency in neuron and prone to oxidizing or other metabolic insults and impairs synaptic plasticity </li></ul><ul><li>High serum glucose --> up regulate the tau kinase, glycogen synthase kinase 3  and reduce levels of insulin-degrading enzyme in the AD’s brains </li></ul><ul><li>Thiazolidine (PPAR agonist)  activate insulin responsive gene transcription  had significant effects in some AD patients </li></ul>
    44. 46. Mitochondrial Dysfunction Insulin Signaling Pathway <ul><li>It is not clear whether signaling is up-regulated (compensatory) or down-regulated (pathologic) in AD </li></ul>Douglas C.Wallace , et. al., Annu. Rev. Pathol. Mech. Dis. 2010.5:297-348.
    45. 47. ALZYMER’S DISEASE <ul><li>DEFINING PHATOLOGICAL AND BIOCHEMICAL CARACTERISTICS </li></ul><ul><li>Amyloids plaques(extracellular) </li></ul><ul><li>Neurofibrillary tangles(intracellular) </li></ul><ul><li>Inflammation(astrocytosis, miccrogriosis, cytokines, complement, acute phase inflammatory proteins) </li></ul><ul><li>Selective neuronal degeneration </li></ul><ul><li>Synaptic loss </li></ul><ul><li>Multiple neurotransmitter deficits </li></ul>
    46. 48. VASCULAR EFFECTS IN ALZHEIMER’S DISEASE
    47. 49. VASCULAR EFFECT OF ALZHEIMER’ S DISEASE <ul><li>Vascular dementia </li></ul><ul><li>Cerebral amyloid angiopathy </li></ul><ul><li>Capillary abnormalities </li></ul><ul><li>Disruption of blood brain barrier </li></ul><ul><li>Large-vessel atheroma </li></ul>None of these changes alone explain the symmetric reductions of cerebral blood flow in patients with Alzheimer's disease
    48. 50. Cerebral hypoperfusion and clinical onset of dementia: the Rotterdam Study. Ruitenberg A, Ann Neurol. 2005 <ul><li>Cerebral blood flow (CBF) velocity is decreased in patients with Alzheimer's disease. </li></ul><ul><li>It is being debated whether this reflects decrease because of advanced neurodegeneration or cerebral hypoperfusion contributes to dementia </li></ul><ul><li>Although they cannot prove that this is caused by preclinical neurodegeneration leading to hypoperfusion </li></ul><ul><li>But they suggest that cerebral hypoperfusion precedes and possibly contributes to onset of clinical dementia </li></ul>
    49. 51. Atherosclerosis of Cerebral Arteries in Alzheimer Disease Alex E. Roher, MD PhD; Stroke. 2004 <ul><li>Large-vessel atheroma </li></ul><ul><li>Vascular disease underlies Alzheimer dementia </li></ul><ul><li>Atherosclerotic lesions and large leptomeningeal vessels were found to correlate with Alzheimer disease (AD) clinical diagnosis and neuropathology </li></ul><ul><li>AD pathology is the complex end result of slowly evolving vascular disease and parenchymal lesions </li></ul>
    50. 52. Inflammation and Mechanism of A β Clearance
    51. 53. VASCULAR CHANGED IN ALZHEIMER’S THERAPY <ul><li>Immunotherapy </li></ul>Angiotensin-converting- enzyme inhibitor Folic acid Advance glycation end product inhibitor The reduction of cognitive decline Reduced homocyteine level and may lower the risk of AD but not improve cognitive Phase 2 study in mild-to- Moderate AD Might be concern increased vascular amyloid, microhemorrhages, vasogenic edema
    52. 54. Chronic microglia activation and macrophage infiltration in Alzheimer’s disease http://www.nature.com/nrn/journal/v6/n9/fig_tab/nrn1725_F2.html
    53. 55. Inflammatory-activated glia co-cultured neurons http://www.neuroscience.cam.ac.uk/directory/profile.php?gcb3
    54. 56. Some components of the inflammatory to CNS degeneration http://www.gladstone.ucsf.edu/wp/2009/10/inflammationalzheimers/
    55. 57. Inflammatory responses and neurodegeneration http://www.gladstone.ucsf.edu/wp/2009/10/inflammationalzheimers/
    56. 58. Neurotoxic and neurotrophic action of microglia and astrocytes McNally L, Bhagwager Z, Hannestad J, CNS Spectr, Vol 13 NO.6. 2008.
    57. 59. Using the inflammatory response against AD http://www.gladstone.ucsf.edu/wp/2009/10/inflammationalzheimers/
    58. 60. INFLAMMATION IN ALZHEIMER’S THERAPY <ul><li>A β Immunization, TNF- α and </li></ul><ul><li>Complement factor blocker agents </li></ul>Nonsteroidal anti- Inflammatory agent Lower the risk’s of AD and slow progression of disease the mechanisms of action is selective reduction of A β 42, Inhibition of COX 2 or prostaglandin receptor, stimulation of phagocytosis by microglia (Only in prospective Observation study) Not show evidence of reducing The risk of AD or slowing cognitive decline Nonsteroidal anti- Inflammatory agent and derivative( Tarenflubil ) Being investigated
    59. 61. Calcium Presenilin mutation Disrupt calcium homeostasis Calcium in endoplasmic reticulum Release calcium into cytoplasm Alzheimer’s disease A β level
    60. 62. Calcium <ul><li>In late stage of </li></ul><ul><li>Alzheimer’s disease </li></ul>Glutaminergic receptor activation + Cytosolic calcium Calcium – release channel in ER
    61. 63. Axonal – transport deficit <ul><li>Kinesin family drive vesicles and mitochondia destined for the synaptic terminal along axonal microtubules. </li></ul><ul><li>BACE 1 ( amyloid precursor protien) and presenilin 1 were reported to undergo fast anterograde transport into terminal fields where A β and proteolytic derivatives are released </li></ul>
    62. 64. Axonal – transport deficit Impairment of transport Amyloid precursor protein, vesicle and kinesin Exonal swelling, A β deposition and neurodegeneration
    63. 65. Aberrant Cell-Cycle Reentry http://www.nature.com/nrn/journal/v8/n6/box/nrn2097_BX2.html  Oxidative stress  DNA-damaging agents
    64. 66. Cholesterol Metabolism http://en.wikibooks.org/wiki/File:Lipid_Raft*.png
    65. 67. Cholesterol Metabolism http://www.rndsystems.com/cb_detail_objectname_WI00_BaceAlzheimers.aspx promoted and clearance from the brain is reduced
    66. 68. Cholesterol Metabolism http://www.gladstone.ucsf.edu/wp/2009/10/alzheimersandapoe/
    67. 69. Cholesterol Metabolism High serum cholesterol levels Alzheimer’s disease <ul><li>Statins </li></ul><ul><li>reduce the membrane pool of free cholesterol </li></ul><ul><li>reductions in inflammation </li></ul><ul><li>- up-regulation of α-secretase and vascular function </li></ul>
    68. 70. Definition <ul><li>Advanced glycation end products ( AGEs ) are formed as a result of nonenzymatic reactions between intracellular glucose - derived dicarbonyl precursors ( glyoxal, methylglyoxal, and 3deoxyglucosone ) with the amino groups of both intracellular and extracellular proteins </li></ul>
    69. 71. <ul><li>Effective treatment for sporadic Alzheimer’s disease rests on </li></ul><ul><li>Translation of the disease pathways </li></ul><ul><li>Additional molecular mechanisms or new risk genes (eg. Apolipoprotein J) </li></ul>
    70. 72. <ul><li>Eg, of recently discovered proteins encoded by these risk genes include - </li></ul><ul><li>Apoliprotein J(clusterin) </li></ul><ul><li>TOMM 40 </li></ul><ul><li>Sortillin-related receptor </li></ul><ul><li>levels are reduced in the brain of patients with AD and mild cognitive impairment </li></ul>
    71. 73. <ul><li>Another potential risk factor for sporadic AD </li></ul><ul><li>(General anesthesia) promote- </li></ul><ul><li>tau insolubility </li></ul><ul><li>A β oligomerization </li></ul><ul><li>Deficiency of estrogen in brains of post-menopausal women </li></ul><ul><li>Chronic activation of the glucocorticoid axis </li></ul>
    72. 74. <ul><li>Normally tau protein is soluble and abundant in axons </li></ul><ul><li>Hyperphosphorylated tau is insoluble and lacks affinity for microtubules and self-associates into paired helical structures </li></ul>
    73. 75. <ul><li>It’s already observed that the correlation between the levels of A β oligomers in the brain and severity of cognitive defect in AD </li></ul><ul><li>Oligomers and protofibrils are considered potent blockers of long-term potentiation that involved in memory formation </li></ul>
    74. 76. <ul><li>But does these factors lead to amyloid deposition and tauopathy in human is still in question? </li></ul><ul><li>Recent studies point to brain atrophy and other pathologic conditions, not severe amyloid or tangle load, in accounting for dementia in the oldest ones </li></ul>
    75. 77. <ul><li>Prospective studies show that cognitive leisure activity and training can lower the risk of demensia </li></ul><ul><li>Possible that many of these mechanisms (including the amyloid hypothesis) are minor or wrong and some critical aging-related process is the disease trigger </li></ul>

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