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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS076794-05
Application #
8900365
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Corriveau, Roderick A
Project Start
2011-09-30
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Southern California
Department
Physiology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90032
Guillot-Sestier, Marie-Victoire; Town, Terrence (2018) Let's make microglia great again in neurodegenerative disorders. J Neural Transm (Vienna) 125:751-770
Mori, Takashi; Koyama, Naoki; Tan, Jun et al. (2017) Combination therapy with octyl gallate and ferulic acid improves cognition and neurodegeneration in a transgenic mouse model of Alzheimer's disease. J Biol Chem 292:11310-11325
Andreasson, Katrin I; Bachstetter, Adam D; Colonna, Marco et al. (2016) Targeting innate immunity for neurodegenerative disorders of the central nervous system. J Neurochem 138:653-93
Guillot-Sestier, Marie-Victoire; Weitz, Tara M; Town, Terrence (2016) Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease. J Vis Exp :
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
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
Guillot-Sestier, Marie-Victoire; Doty, Kevin R; Town, Terrence (2015) Innate Immunity Fights Alzheimer's Disease. Trends Neurosci 38:674-681
Heneka, Michael T; Carson, Monica J; El Khoury, Joseph et al. (2015) Neuroinflammation in Alzheimer's disease. Lancet Neurol 14:388-405
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
Gate, David; Danielpour, Moise; Rodriguez Jr, Javier et al. (2014) T-cell TGF-? signaling abrogation restricts medulloblastoma progression. Proc Natl Acad Sci U S A 111:E3458-66

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