Alzheimer’s Disease Neurobiology

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

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

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.

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?

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

Model of how reduced NGF signaling affects Abeta

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

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

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.

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

A model of caspase-3 bifurcation switch.

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?

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

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

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

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

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

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)

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

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

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

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

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

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

Model of how inflammation feeds forward in AD pathology