While amyloid plaques and neurofibrillary tangles are Alzheimer's disease (AD) defining features, Alzheimer himself originally identified a third pathology? inflammation of the brain's glial support cells. Neuroinflammation in AD is characterized by reactive astrocytes and microglia that surround amyloid plaques and chronically secrete inflammatory innate immune cytokines. The dominant view for decades has been that all forms of inflammation damage the AD brain. Yet, non-steroidal anti-inflammatory drugs failed to produce a positive signal for AD primary prevention. This raises a fundamental question: should we be blocking or possibly even promoting inflammation as an AD therapeutic? While the focus has mainly been on pro-inflammatory cerebral innate immunity, little attention has been paid to factors that curtail peripheral innate immune responses. The unifying theme of our work is that `rebalancing' peripheral innate immunity to homeostasis by releasing immunosuppression will limit AD progression. Strikingly, our focus on innate immunity in AD has just recently been validated by genome-wide association studies. These results have taken the field by storm; identifying clusters of AD risk alleles in core peripheral macrophage pathways. As a key cytokine suppressor of innate immunity and inflammation, transforming growth factor-beta (TGF-?) mRNA abundance is increased in AD patient brains. We hypothesize that the AD brain over- compensates to pro-inflammatory signals by producing these abnormally high levels of TGF-?. Paradoxically, this sets up early, low-level and chronic neuroinflammation that fails to support amyloid-? (A?) clearance. I and my team have shown in published and preliminary data that genetic or pharmacologic blockade of TGF-?- Smad 2/3 signaling in peripheral macrophages leads to brain entry of these cells and A? phagocytosis; sparing neurons from injury and restoring learning and memory. To further explore this theme, we have now generated the TgF344-AD rat that recapitulates cognitive impairment and the full array of human AD pathological features: neuroinflammation, plaques, tangles, and frank neuronal loss.
In AIM 1, we will use non-invasive longitudinal imaging approaches to determine whether early neuroinflammation preempts later cognitive impairment, A? deposition, structural connectivity changes and neuronal death in TgF344-AD rats.
AIM 2 is designed to longitudinally evaluate if blocking peripheral innate immune TGF-? signaling licenses A? phagocytosis and mitigates AD-like changes by delivering cutting- edge nanoparticles containing small molecule TGF-?-Smad 2/3 signaling inhibitor payload to hematogenous macrophages. Finally, we will pharmacologically delete peripheral macrophages to definitively establish if they are responsible for the beneficial effects of TGF-? signaling inhibition. While AD animal model studies are typically limited by cross-sectional designs, this project will break this barrier by coupling the most advanced multimodal, longitudinal brain imaging with peripheral TGF-? signaling inhibition in the TgF344-AD rat.

Public Health Relevance

Alzheimer?s disease (AD) now afflicts more than 5 million Americans, and an effective treatment or cure does not exist. Understanding innate immune and inflammatory mechanisms of AD is crucial for developing safe and effective therapeutics. For the first time, we propose to combine the most advanced longitudinal, multi- modal imaging approaches in our novel TgF344-AD rat model with an experimental therapy to return innate immunity to homeostasis by blocking transforming growth factor-beta signaling in peripheral macrophages.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Mcgavern, Linda
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University of Southern California
Schools of Medicine
Los Angeles
United States
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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
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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 :
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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
Guillot-Sestier, Marie-Victoire; Doty, Kevin R; Town, Terrence (2015) Innate Immunity Fights Alzheimer's Disease. Trends Neurosci 38:674-681
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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