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Class Lecture Notes 14-21 - Feb 6-March 4 - PSYCH 2NF3

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Gautam Ullal

PSYCH 2NF3 2013 Lecture 14 21Feb 6March 4Alzheimers Disease Genetics and Pathogenesis of EarlyOnset ADAmyloidPrecursor Protein o Amyloidprecursorprotein APPtransmembrane protein important for the normal development and plasticity of synapse o Goes into cytoplasm and a bit outside o It requires to be cleaved by enzyme secretases o Depending upon cleavagesites there aremid membranefar from membrane andinside membrane secretase enzymes o Cleavage by secretase coupled with secretaseamyloid peptide A which is toxic and detrimental to dendrites axons and synapseAmyloid plaques deposited in the synapseneed amyloid proteins to be transported along axon to cell body because it has a functional role activate nucleus neurotrophic factors if it cant be transported cell will dieFormation of abnormal helical precipitates inside the axon Neurofibrillary Tangles o Cleavage by secretase produces a nontoxic biologically useful amyloid byproduct with neurotrophic propertieso All 3 secretases are importantdifferent pieces of the peptide have different functions o In order for peptide to work need 2 enzymes o As long asandare not paired oshouldnt come first Genetics and Pathogenesis of LateOnset and Sporadic AD95 of casesSporadicno clear pattern of incidence hearandthereApolipoprotein Eimportant for cholesterol transport and in maintaining synaptic function and clearing any amyloid deposits and neurofibrillary tangles o Produced by astrocytesApo E4apolipoprotein E allele associated with increased risk of amyloid deposits toxic o Associated with lateonset and sporadic ADA Global Problem of an Ageing PopulationAge s the major risk factor for ADThe risk increases with each decade of adult life2040 of people 85 years have ADRisk Factors for ADAgingFamily history of ADHead injuryLow educational attainmentFamily history of Downs syndromeGenderfemales more prone than malesThe Tauists and BAPtistisTauaggregation tanglesbetaamyloid plaques which comes firstNeuroanatomically BetaAmyloid Plaque closely corresponds to Taupathology Tauopathy in polymodal areas is sensitive to BetaAmyloid Plaques o Polymodal areascortical sensory areas that integrate various sensations eg touch and vision o If betaamyloid is in polymodal areas it enters tau pathologyDistribution of Neurodegenerative Changes in ADBraak stages follow a Dominopattern of taudeposition in axons a Entorhinal cortexthe major input into hippocampus where we first see tangles b Hippocampus c Posterior parietalpolymodal neocortex sensory areasassociation cortex d Frontal cortex e Primary sensory and primary motor areas Six stages of progression defined by pathology and molecular biology o Amyloid plaque formation and neurofibrillary tangle deposition follow a similar progressive neuroanatomical path1 PSYCH 2NF3 2013 Stage I and II Transentorhinal Subclinical o No clinical signsStage III and IV Progressed to Limbic Cortex o Mild Cognitive Impairmentanterograde amnesia inability to form new memories loses way spatial memory affected because of hippocampal involvement o Right hippocampusparticularly activated when we do spatial learning and orientation navigationActivated when we do spatial recallEg hypertrophy in right brain of cab driver cab driver recall a map o Left hippocampusparticularly activated when we do wordrecallo Hippocampus and spatial memorySelectively knocking out NMDA type of glutamate receptor in hippocampus interferes with Morris Water Maze Spatial Learning Animal disoriented because knocked out gene in hippocampus involved in spatial learning processKnocking in the gene restores the Morris Water Maze Spatial Learning o Story of HMseverely epileptic for several years not controlled with medicinesBilateral Temporal Lobe resection done in 1953 controlled the seizures completelyFollowing surgeryAnterograde amnesiacould not form new memories inability to remember any event subsequent to the surgeryNormal memory for events long prior to surgery retrogradeNormal IQNormal languageNormal social behaviour 2 PSYCH 2NF3 2013 Scovilles Historical Surgery on HMo Possible outcome of brain injury on old and new memoriesNote retrograde memory is less effected with old memories being relatively preserved Stave V and VI Progressed to association neocortex prefrontal frontal language areas primary sensory and motor areas o Impairment in abstract thinking language personality changes retrograde amnesia forgets people social issues motor paralysisGrey matter loss with Braak using MRI3
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