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MIT 9 01 - Age-depedent neurodegenerative disorder

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MIT OpenCourseWare http://ocw.mit.edu 9.01 Introduction to Neuroscience Fall 2007 For information about citing these materials or our Terms of Use, visit: http://ocw.mit.edu/terms.Age-depedent neurodegenerative disorder with cortical dementia - Alzheimer’s disease Li-Huei Tsai, Ph.D. Howard Hughes Medical Institute Picower Institute for Learning and Memory Department of Brain & Cognitive Sciences Stanley Center for Psychiatric Research, Broad Institute1100 years of Alzheimer’ss disease Dr. AAlois Alzheimer AAuguste Deter “Alzheimer: What is your name? Auguste D: Auguste Alzheimer: Last name? Auguste D: Auguste Alzheimer: What is your husband’s name? Auguste D: Auguste I think Alzheimer: How long have you been here? Auguste D: 3 weeks (it was her 2nd day in the hospital)” (Translated from A Alzheimer, 1906)Alzheimer’s disease Affect 4.5 million people in US (10% over the age of 65 and 45-50% over the age of 85); probably 20-30 million people world wide. The number is expected to triple over the next few decades. Symptoms: loss of recent memory, forgetfulness (mild cognitive impairment, MCI), transient periods of confusion, restlessness, word finding difficulty, spatial disorientation, progressive deterioration of memory and other cognitive functions, dementia. From MCI to marked dementia may take several years. Pathology: severely atrophied cerebral hemispheres and dilated ventricles; loss of neurons in selected brain regions; neurofibrillary tangles; amyloid plaquesLLecture Outline •Pathological features of AD •Pathogenesis of AD •�-amyloid and learning impairment •The relationship of tau and AD •Cdk5 and AD •Diagnosis of AD •Therapeutic intervention of ADAlzheimer’s disease -- Brain Atrophy Autopsy Brain MRI Scan ((AAddaapptteeddffrroommMM..MMaattttssoonn,,22000044))Normal brain Alzheimer’s brain Courtesy of Mark P. Mattson. Used with permission.Amyloid plaques and neurofibrillary tangles (NFT) NNeuuroofibbriilllarry ttannglless (NNFTT)AAmyylooidd pllaqquees DDeppossittioo epptiidees P-Tau Tangles APP Aß Plaques TauNew Text . Images courtesy of Elsevier, Inc., http://www.sciencedirect.com. Used with permission .New Text Left: Price, J. L., et al. Neurobiology of Aging 30 , no. 7 (July 2009): 1026-1036. Right: Gorrie, C. A. Accident Analysis & Prevention 39, no. 6 (2007): 1114-1120. .NNFFTTppaatthhoollooggyyBBrraaiinnaattrroopphhyywhite matter cortex hippocampal formation Brain areas initially affected by AD pathology(Sigmaaldrich.com) Mutations in APP, PS1 and PS2 cause familial Alzheimer’s disease (FAD) : Image removed due to copyright restrictions. See Figure 1 in Prostak, L. et al. "ß Secretase (BACE1) Activity Assay Kit: A FRET Based Assay Designed for BACE1 Inhibitor Screening." http://www.sigmaaldrich.com/life-science/cell-biology/learning-center/bace1-assay-kit.html.NH2 COOH TM 69518 E amyloid precursor protein (APP) D C83p3APPs E C99 C89APPs APPs J AE  AE  AICDGenetics of familial Alzheimer’s disease Missense mutations in APP - found in about 2 dozens of families - mutations are usually around D-, E- or J-secretase sites. These mutations lead to alterations of APP processing and increased AE production. -trisomy 21 in Down’s syndrome leads to the premature occurrence of AD neuropathology during middle adult years and overproduction of AE40 and AE42. Missense mutations in the presenilins: the most common cause of autosomal dominant familial AD - chrom14, PS1, missense mutations usually lead to early onset AD (40s-50s) >75 different mutations found -chrom1, PS2, early onset, 3 different mutations identified - PS mutations cause increase in AE42/ AE40 ratioRisk factors for Alzheimer’s disease The ApoE4 allele is a major genetic risk factor for late-onset AD - chrom19 - one E4 allele increases the likelihood of developing AD by 2-5 fold - two E4 alleles increase the likelihood of developing AD by >5 fold - however, there are also individuals with both E4 alleles without developing AD - mechanism unknown, likely enhances the deposition or decreases the clearance of Ab peptides. Other genetic alternations predisposing to AD - chrom12, risk factor for late onset, alteration in or near a2-macroglobulin - chrom10q, late onset - others, likely to be moreLearning impairment in APPFAD mouse models • PDAPP (London mutation) mice exhibit age-related deficits in learning a series of spatial locations (Chen et al, 2000) • Tg2576 (Swedish mutation) mice exhibit age-related impairment in spatial reference memory (Westerman et al, 2002; Lesne et al, 2006) • AbetaE22G (Arctic mutation) mice display deficits in water maze tasks (Cheng et al, 2007) • In many of the APPFAD models, learning impairment is detected prior to the manifestation of plaque pathology (Lesne et al., 2006)The amyloid species that impairs learning • In middle-aged Tg2576 (Swedish mutation) mice extracellular accumulation of a 56 kDa soluble Abeta assembly (Abeta*56) correlates with memory deficits (Lesne et al, 2006) • Introduction of purified Abeta*56 into young rats impairs spatial memory (Lesne et al, 2006) Courtesy of Karen H. Ashe. Used with permission.AE in synaptic function • Secreted oligomers of AE potently inhibit hippocampal LTP in anesthetized rats (Walsh et al, 2002) • Neuronal activity can modulate formation and secretion of AE and AE can decrease AMPA and NMDA-dependent currents (Kamenetz et al, 2003) • Oligomers of AE can induce reversible synapse loss by modulating an NMDAR signaling pathway (Shankar et al., 2007) • APPFAD mice have spontaneous nonconvulsive seizure activity in cortical and hippocampal networks, increased GABAergic sprouting, enhanced synaptic inhibition, and synaptic plasticity deficits in the dentate gyrus (Palop et al, 2007)Neurofibrillary tangles (NFT) Non-membrane bound masses of fibers known as paired helical filaments (PHF) in the cell bodies of select neurons PHF is made primarily, if not solely of the microtubule associated protein tau, in the hyperphosphorylated state In general, the neurofibrillary pathology and neuronal loss associate closely in affected brain regions Neurofibrillary pathology is also present in other neurodegenerative disorders including Down’s syndrome, fronto-temporal dementia, Parkinson’s disease, and progressive supranuclear palsy.Tau Alzheimer’s Disease and Tau Tau P Microtubule-bound tau Cdk5 GSK-3ȕ MAPK MARK etc Paired Helical Filament (PHF-1)


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