1. Alzheimer’s Disease Neurobiology

2. Active Research Areas in AD
Cholinergic/NGF/BDNF
Amyloid beta
Tau
ApoE

3. Cholinergic Hypothesis
Proposed that inability to obtain or use NGF underlies the demise of these CBF neurons.
CBF neurons depend upon NGF for their survival and maintenance.
Basal forebrain cholinergic (CBF) cell death correlates with disease severity, pathology, and synapse loss.
Cholinergic Hypothesis

4. Lesions of the NBM lead to sleep deficit and memory deficits in mid-aged rats. Neurons in the BFB depend upon trophic support via NGF for their survival.

5. NGF is produced in the cortex and hippocampus
NGF is produced in the cortex and hippocampus. But the high affinity trkA receptor is decreased in both cortex and CBF neurons. P75 low affinity receptor is increased or unchanged. May lead to apoptosis. Levels of NGF in the CBF cell bodies is reduced. Failure of transport? Binding? Complex?

6. Age related decline in NGF transport
1= NGF only, 2=ChAt only (small shrunken cells), 3=double labeled.
NGF injection and transport to ChAT expressing neurons

7. Model of how reduced NGF signaling affects Abeta

8. Amyloid Hypothesis
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

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

10. 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
Synaptic plasticity
LTP and dendrite complexity in the HPC
So possibly both gain and loss of function effects of APP mutation.

11. Ab may affect a shift in caspase-3 activity with age
Timing and intensity of caspase 3 activation determine its activity.

12. A model of caspase-3 bifurcation switch.

14. APP knockout mice 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
Bottom line: consequences of losing APP are subtle. Have to look hard for defects. Gain or loss of function in AD?

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

16. Triple Transgenic Mice (3XTg)
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
LaFerla and Oddo, 2005

17. Pathology in the 3X TG mouse model of AD
Figure 4. A􏰀 Deposition Initiates in the Neocortex and Progresses to the Hippocampus (A) Low-magnification view of neocortex from an aged 3􏰄Tg-AD mouse following staining with A􏰀42-specific antibody.
(B and C) Higher-magnification views of section in (A) showing extracellular plaque and intraneuronal A􏰀 immunoreactivity following staining with A􏰀42-specific antibody. (D) Low-magnification view of hippocampus from 18-month-old 3􏰄Tg-AD mouse with the A􏰀42-specific antibody showing the number of A􏰀42-reactive plaques.
(E and F) High-magnification view of subicular/CA1 region of panel shown in (D), and (F) a serial section following thioflavin S staining. (G) Double labeling immunohistochemistry in which astrocytes are reacted with anti-GFAP antibodies and stained brown with DAB, and A􏰀 is reacted with antibody 6E10 and developed with true blue. (H and I) A􏰀 and tau colocalize to many of the same pyramidal neurons. Low- (H) and high- (I) magnification views in which A􏰀 was immunostained with 6E10 followed by detection with true blue, whereas tau was immunostained with antibody HT7 and detected using DAB (brown staining). Mouse ages are 12 months, (G)—(I), and 18 months, (A)—(F).
12 months of age

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

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

21. BACE inhibitors
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)

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

23. BACE-1 inhibitors reduce Ab
Cell culture model, neuronal derived cell line expresses the Swedish APP mutation
2006 GlaxoSmithKline, J. Neurochem. (2007) 100, 802–809

24. BACE knockout mice Philipson et al 2009
Reduced pathology in BACE-1 knockout, 3rd column. E-H Ab antibody, I-L Ab40, M-P Ab42.
Philipson et al 2009

25. BACE-1 -/- rescues memory defect in AD transgenic mice
Social recognition. Time spent exploring should the novel animal should increase if an animal remembers he has explored before. Defective in Tg2576, rescued by loss of BACE-1
WT BACE-1 APPsw APPsw+
BACE-1D
Ohno et al, 2004 Neuron

26. Alternative Treatment: HDAC Inhibitor
Nature 447, (10 May 2007)

27. Inflammation in AD Pro-inflammatory Anti-inflammatory, protective
control (should be equal in all)

28. Model of how inflammation feeds forward in AD pathology