DESCRIPTION (provided by applicant): 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.