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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Corriveau, Roderick A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
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
Doty, Kevin R; Guillot-Sestier, Marie-Victoire; Town, Terrence (2015) The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive? Brain Res 1617:155-73
Guillot-Sestier, Marie-Victoire; Doty, Kevin R; Gate, David et al. (2015) Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85:534-48
Guillot-Sestier, Marie-Victoire; Doty, Kevin R; Town, Terrence (2015) Innate Immunity Fights Alzheimer's Disease. Trends Neurosci 38:674-81
Gate, David; Danielpour, Moise; Rodriguez Jr, Javier et al. (2014) T-cell TGF-β signaling abrogation restricts medulloblastoma progression. Proc Natl Acad Sci U S A 111:E3458-66
Weitz, Tara M; Gate, David; Rezai-Zadeh, Kavon et al. (2014) MyD88 is dispensable for cerebral amyloidosis and neuroinflammation in APP/PS1 transgenic mice. Am J Pathol 184:2855-61
Mori, Takashi; Koyama, Naoki; Segawa, Tatsuya et al. (2014) Methylene blue modulates β-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice. J Biol Chem 289:30303-17
Guillot-Sestier, Marie-Victoire; Town, Terrence (2013) Innate immunity in Alzheimer's disease: a complex affair. CNS Neurol Disord Drug Targets 12:593-607
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
Cohen, Robert M; Rezai-Zadeh, Kavon; Weitz, Tara M et al. (2013) A transgenic Alzheimer rat with plaques, tau pathology, behavioral impairment, oligomeric aβ, and frank neuronal loss. J Neurosci 33:6245-56

Showing the most recent 10 out of 15 publications