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Alzheimer’s Disease Neurobiology

Alzheimer’s Disease Neurobiology. Active Research Areas in AD. Cholinergic Hypothesis. Age related decline in NGF transport. NGF injection and transport to ChAT expressing neurons. Model of how reduced NGF signaling affects Abeta.

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Alzheimer’s Disease Neurobiology

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  1. Alzheimer’s Disease Neurobiology

  2. Active Research Areas in AD

  3. Cholinergic Hypothesis

  4. Age related decline in NGF transport NGF injection and transport to ChAT expressing neurons

  5. Model of how reduced NGF signaling affects Abeta

  6. Amyloid Beta (Ab) is the primary component of senile plaques Senile plaques disrupt neuronal function and lead to neuronal death Mutations in APP (amyloid precursor protein) cause familial AD Amyloid Hypothesis

  7. APP Processing • Secretases: • Alpha=good • Beta=bad • Gamma=neutral -PS1 & PS2

  8. What does APP do? • Axonal transport, particularly of complexes containing its proteases, b- and g-secretase • Via kinesin interaction • Cell adhesion • Synapse formation? • Development • Cell growth • Development • Synaptic plasticity • LTP and dendrite complexity in the HPC

  9. Ab may affect a shift in caspase-3 activity with age

  10. Viable Indistinguishable from WT Defect in passive avoidance learning with age Defect in retinal wiring (does not affect acuity) Defect in limb strength Redundancy with APPLP1 and 2 APP knockout mice

  11. Familial Mutation Mice • APP (TG2576) • PS1 • PS2 • Combination Mice • PS1 + APP • Features: Abeta plaques, loss of synapses, spatial memory impairments, gliosis Alzheimer’s disease models

  12. Homozygous PS1, Tg2576 APP, P301Ltau • Abeta and tau pathology closely follows human AD in timing and location • LTP deficits precede Abeta deposits • Intracellular Abeta correlates with cognitive decline • Cognitive decline begins at 4 months • Abeta immunotherapy delays memory decline Triple Transgenic Mice (3XTg) LaFerla and Oddo, 2005

  13. Pathology in the 3X TG mouse model of AD 12 months of age

  14. LTP defect in 3X Tg mouse model (red) Blue=Control, Green=PS1 only, Yellow=2X Tg, Red=3x tg

  15. Rational design Hypothesis driven pathway interventions Short life span of rodents Less complex brain anatomy, neuron number Compare current vs. “alternative” treatments Can animal models be used to develop better treatments?

  16. Rationale: Abeta is toxic to neurons, promotes inflammation, and probably affects tau pathology • Reducing Abeta production should benefit not only symptoms, but disease progression (stop feed-forward cycles) BACE inhibitors

  17. Targeting the amyloid production pathway in AD Masters et al, Nat Rev Dis Prim 2015; Vol 1: 1-18

  18. BACE-1 inhibitors reduce Ab 2006 GlaxoSmithKline, J. Neurochem. (2007) 100, 802–809

  19. BACE knockout mice Philipson et al 2009

  20. BACE-1 -/- rescues memory defect in AD transgenic mice WT BACE-1 APPsw APPsw+ BACE-1D Ohno et al, 2004 Neuron

  21. Alternative Treatment: HDAC Inhibitor Nature 447, 151-152 (10 May 2007)

  22. Inflammation in AD

  23. Model of how inflammation feeds forward in AD pathology

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