Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of A? peptides as 'senile'?-amyloid plaques, neuropathology, and neuroinflammation. Brain inflammation ultimately fails at mitigating AD pathology. However, broadly inhibiting inflammation has not produced a positive signal for AD primary prevention. This and other evidence has prompted our overarching hypothesis: that re-balancing inflammation as opposed to shutting it off completely may be beneficial for AD. The cardinal suppressive cytokine transforming growth factor-? (TGF-?) keeps overly exuberant inflammation in check to guard against bystander tissue injury. Others have demonstrated that TGF-?1 mRNA is ~3-fold higher in AD patient brains vs. healthy elderly controls, potentially biasing toward a suppressive milieu that is ineffective at restricting cerebral amyloidosis. Our published and preliminary data using genetic and pharmacologic approaches in mouse models of cerebral amyloidosis suggest that re-balancing (by inhibiting) TGF-? signaling in hematogenous mononuclear phagocytes promotes their brain infiltration and A?/?-amyloid clearance. We have developed a working hypothesis that re-balancing TGF-? signaling may restrict AD-like pathology. A key limitation to fully testing this hypothesis has been unavailability of an animal model that faithfully recapitulates human AD. To overcome this, we have developed a novel rat model of AD (line TgF344-AD) based on co-expression of mutant human amyloid precursor protein and presenilin-1, each independent causes of early-onset familial AD. Strikingly, TgF344-AD rats manifest age-dependent cerebral amyloidosis that precedes gliosis, tauopathy, neuronal loss and cognitive disturbance. Unlike A?-driven transgenic mice, which model cerebral amyloid well but not the full spectrum of AD pathologies, these transgenic rats develop progressive neurodegeneration of the Alzheimer type. This next-generation AD rat model will enable basic and translational AD research, and offers a unique opportunity to evaluate the 'amyloid cascade hypothesis'of AD. The overarching goal of this proposal is to utilize TgF344-AD rats to evaluate whether pharmacologic inhibition of peripheral TGF-? signaling mobilizes hematogenous A? mononuclear phagocytes to restrict AD- like pathology. The focus of Specific Aim 1 will be to assess whether peripheral blockade of TGF-?-Smad 2/3 signaling prevents or slows cerebral amyloidosis leading to neuropathology and cognitive decline.
In Specific Aim 2, we will determine if peripheral TGF-?-Smad 2/3 pathway inhibition treats established Alzheimer-type disease and reduces cognitive impairment.
Specific Aim 3 will evaluate whether beneficial effects of peripheral TGF-? signaling blockade in transgenic Alzheimer rats are macrophage-dependent. Our hypotheses in this aim are two-fold: 1) that peripheral TGF-? signaling inhibition will promote brain infiltration of hematogenous A2 phagocytes with an 'alternate M2'activation profile and 2) that deletion of hematogenous macrophages will block the beneficial effects of peripheral TGF-?-Smad 2/3 inhibition on Alzheimer pathology.

Public Health Relevance

There are now over 3 million Americans afflicted with Alzheimer's disease, a figure that is projected to increase to 9 million by 2050, underscoring a rapidly developing public health problem. We propose that re-balancing TGF-? signaling in immune cells allows these cells to restrict the disease. If results from our Alzheimer's transgenic rat model establish the importance of this pathway, this could unveil a new therapeutic approach.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Glia Study Section (CMBG)
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Corriveau, Roderick A
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Cedars-Sinai Medical Center
Los Angeles
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Daianu, Madelaine; Jacobs, Russell E; Weitz, Tara M et al. (2015) Multi-Shell Hybrid Diffusion Imaging (HYDI) at 7 Tesla in TgF344-AD Transgenic Alzheimer Rats. PLoS One 10:e0145205
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Guillot-Sestier, Marie-Victoire; Doty, Kevin R; Town, Terrence (2015) Innate Immunity Fights Alzheimer's Disease. Trends Neurosci 38:674-81
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Mori, Takashi; Koyama, Naoki; Guillot-Sestier, Marie-Victoire et al. (2013) Ferulic acid is a nutraceutical β-secretase modulator that improves behavioral impairment and alzheimer-like pathology in transgenic mice. PLoS One 8:e55774
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