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Download Plaque and tangle distribution at different stages of Alzheimer`s
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Plaque and tangle distribution at different stages of Alzheimer’s disease progression (Braak staging) Prodromal Tangles Amyloid plaques Early-Moderate Moderate -Late Braak & Tredici Acta Neuropath 2011 Spread of tau pathology follows a distinct neuroanatomical path that suggests network connectivity EC directed expression of (mutant) tau Young (~10 mo) Old (~22 mo) Parietal cortex Parietal cortex so sp SR sp so SL-M SR SL-M H GC H GC O M I Perirhinal cortex O M I Perirhinal cortex subiculum subiculum Lateral EC Lateral EC Medial EC Medial EC MC1 antibody – human specific, recognizes an abnormal conformation of tau POSSIBLE MODES OF SPREAD 1) Dysfunction in cell A induces dysfunction and de novo pathology in neighboring cell B 2) Secretion of tau molecules from cell A induces dysfunction and de novo pathology in neighboring cell B 3) Secretion or transfer of tau molecules from cell A to neighboring cell B Propagation to new cells follows abnormal tau conformation “templating” to normal tau and repeat of cycle (c) somatodendritic/synapse degeneration releasing tau into the extracellular space? Tau pathology spreads to monosynaptically connected neurons that do not express human tau - evidence for cell-cell propagation young old GC GC H H GC IML IML MML MML OML Tau pathology can also spread to glia (Hyman et al 2012 OML Small tau aggregates are taken up by neurons and transported anterogradely Cell bodies Axons in grooves Tau β-tubulin III (neuron specific) DAPI 0.4uM hTau40 dimer and trimers for 12 h Axon terminals …and retrogradely where it coalesces in the cell bodies Tau Cell bodies Axons in grooves Accumulation of neurotoxic forms of tau in somatodendritic compartments of EC neurons Disturbance of Tau metabolism Hyperphosphorylation? Altered clearance of pathological forms? Impedance of axonal transport Degeneration of axons in pp Degeneration of somatodendritic compartment in the EC Release of tau into extracellular space from axons , then cell bodies Uptake of tau by surrounding cells IMMUNOTHERAPY to remove extracellular tau Only low molecular weight/small fibrils - monomer, or large fibrils from mature tangles cannot bind to recipient cells Templating to endogenous tau trans-synaptic then transneuronal propagation of pathological tau Widespread tauopathy “Diseases of neural networks” EC-tau EC-APP -Differences between distribution of Abeta/amyloid and tau . -Interactions between Abeta and tau? -Functional outcomes and ordering of events – pathology – function correlations? -Disconnect between where tau or Abeta is generated, and where pathology manifests. -Why do 4R tauopathies (PSP, CBD AGD) affect different regions? -Type of tau (conformers) and impact on cells, or networks affected ? -Why is the EC affected first? Why are layer II stellate neurons affected first? 20+ month old neuropsin-tTA-APP mice make mature and diffuse plaques Abeta 40 Abeta 42 Thio S Pathology distribution in tau and APP mice different – expression pattern of APP/Abeta does not match deposition pattern EC-tau 20+ mo EC-APP 20+ mo MC1 antibody 6E10 antibody