Peripheral TGF-beta Pathway Inhibitor Therapy in Alzheimer's Rats

Cedars-Sinai Medical Center, West Hollywood CA

Investigators

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Abstract

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common dementia, and is hallmarked by deposition of A[unreadable] peptides as 'senile'[unreadable]-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-[unreadable] (TGF-[unreadable]) keeps overly exuberant inflammation in check to guard against bystander tissue injury. Others have demonstrated that TGF-[unreadable]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-[unreadable] signaling in hematogenous mononuclear phagocytes promotes their brain infiltration and A[unreadable]/[unreadable]-amyloid clearance. We have developed a working hypothesis that re-balancing TGF-[unreadable] 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[unreadable]-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-[unreadable] signaling mobilizes hematogenous A[unreadable] mononuclear phagocytes to restrict AD- like pathology. The focus of Specific Aim 1 will be to assess whether peripheral blockade of TGF-[unreadable]-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-[unreadable]-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-[unreadable] signaling blockade in transgenic Alzheimer rats are macrophage-dependent. Our hypotheses in this aim are two-fold: 1) that peripheral TGF-[unreadable] 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-[unreadable]-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-[unreadable] 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.