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 #
1R01NS076794-01
Application #
8221480
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Corriveau, Roderick A
Project Start
2011-09-30
Project End
2016-08-31
Budget Start
2011-09-30
Budget End
2012-08-31
Support Year
1
Fiscal Year
2011
Total Cost
$365,313
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
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
Guillot-Sestier, Marie-Victoire; Town, Terrence (2017) Let's make microglia great again in neurodegenerative disorders. J Neural Transm (Vienna) :
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
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
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
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
Mori, Takashi; Koyama, Naoki; Segawa, Tatsuya et al. (2014) Methylene blue modulates ?-secretase, reverses cerebral amyloidosis, and improves cognition in transgenic mice. J Biol Chem 289:30303-17
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
Guillot-Sestier, Marie-Victoire; Town, Terrence (2013) Innate immunity in Alzheimer's disease: a complex affair. CNS Neurol Disord Drug Targets 12:593-607

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