Microglia can be neuroprotective by phagocytizing amyloid-? (A?), but shift to a destructive phenotype that likely contributes to Alzheimer?s disease (AD) evolution. While greatest attention has been directed toward pro-inflammatory molecules in AD, we have demonstrated that blocking innate immune suppressors mitigates AD-like pathology. Genome-wide association studies have validated the cardinal anti-inflammatory cytokine, interleukin-10 (Il10), as a risk factor for late-onset AD. We show that Il10 deficiency activates mononuclear phagocytes that restrict A? deposits and preserve synaptic integrity and cognitive function. Yet, there is a gap in our knowledge regarding the impact of IL-10 receptor and its proximal downstream mediator, STAT3, on innate immunity in AD. Our overarching hypothesis is that blocking IL-10/STAT3 signaling will return the innate immune system to a physiological state to clear cerebral amyloid and restore cognitive function. We hypothesize that ?re-balancing? the brain inflammatory response to homeostasis by inhibiting innate immune IL-10/STAT3 signaling will restrict Alzheimer-like disease. We have already localized Il10 expression to plaque-associated glia with innate immune properties in the APP/PS1 mouse model of cerebral amyloidosis.
AIM 1 : To evaluate if mononuclear phagocytes are the major responders to IL-10 in the AD context, we will conditionally and inducibly delete (by cre/lox recombination) Il10 receptor (Il10r) or Stat3 in the APP/PS1 innate immune system. Mice will be assessed for behavioral impairment, synaptotoxicity, AD-like pathology and A? phagocytosis by quantitative 3D in silico modeling (q3DISM). RNAseq and ChIPseq on isolated populations of CNS or peripheral mononuclear phagocytes will inform expression and epigenetic modification of hub genes responsive to Il10r or Stat3 deletion.
AIM 2 : To separate systemic from CNS input to Il10r-dependent resolution of AD-like pathology, we will cre/lox inducibly delete Il10r in CNS resident vs. peripheral innate immune compartments of APP/PS1 mice. Brain Il10r deletion will be accomplished with a Cx3cr1-cre/lox approach. Head-sparing bone marrow chimeras will be combined with a Csfr1-cre/lox genetic approach to restrict Il10r deletion to peripheral mononuclear phagocytes in APP/PS1 mice. Cognitive impairment and AD- like pathology will be quantified.
AIM 3 : To assess if systemic or CNS STAT3 inhibition in a human AD rat model rebalances innate immunity to restrict Alzheimer-like disease, TgF344-AD rats developing the full spectrum of AD-like pathologies will be utilized. To distinguish central vs. peripheral innate immune involvement in this scenario, mononuclear phagocyte-targeting nanoparticles loaded with STAT3 inhibitor will be delivered directly into the brain or into the periphery in disease prevention or treatment paradigms. Cognition, AD-like pathology, and A? phagocytosis will be evaluated. This work will define the cellular and molecular mechanisms of innate immune IL-10/STAT3 signaling in AD.
Alzheimer?s disease (AD) currently afflicts more than 5 million Americans, and incidence is rising. Mounting evidence points to dysfunctional innate immunity as a major AD etiologic culprit. We propose to rebalance the innate immune system to homeostasis by genetically or pharmacologically blocking the anti-inflammatory interleukin-10/STAT3 signaling cascade in mouse and rat models of the disease.
|Guillot-Sestier, Marie-Victoire; Town, Terrence (2018) Let's make microglia great again in neurodegenerative disorders. J Neural Transm (Vienna) 125:751-770|