Microglial activation has long been proposed to contribute to the pathogenesis of Alzheimer's disease (AD). Besides causing direct toxic effects on neuronal and synaptic functions, accumulation of amyloid beta (A?) and/or tau stimulates microglial activation and expression of inflammatory cytokines, which can induce further neuronal damage. Blocking the toxic pathway in microglial activation could effectively protect against neurodegeneration. However, the molecular mechanisms modulating the microglial loop remain elusive. Our previous studies in primary cortical cultures suggest that NF-?B activation in microglia plays a critical role in microglial-mediated A? toxicity. Inhibition of NF-?B by SIRT1, a member of the sirtuin family of histone deacetylases, protected against microglia toxicity in A?-treated primary cultures. In AD brains, SIRT1 levels were markedly reduced. SIRT1 expression in cultured microglia was significantly diminished by A? treatment. Based on these findings, we hypothesize that SIRT1 reduction is a key event leading to microglial toxicity in AD and that microglial SIRT1 limits A?-mediated neuronal deficits by suppressing NF-?B activation. To test this hypothesis, we propose three Specific Aims.
In Aim 1, we will inactivate SIRT1 in microglia of mice expressing human amyloid precursor protein (hAPP) and systematically examine how microglial SIRT1 inactivation affects inflammatory responses and A?-related neuronal/behavioral deficits.
In Aim 2, to determine if microglial SIRT1 exerts neuroprotection by suppressing NF-?B activation, we will determine if constitutive activation of canonical NF-?B signaling in microglia of hAPP mice exacerbates the deficits in a manner similar to SIRT1 deletion. In complementary experiments, we will determine if inhibiting NF-?B signaling will ameliorate A?-associated neuronal deficits by infusing a potent NF-?B inhibitor in the brain or injection of a viral vector that inhibits NF-?B in microglia.
In Aim 3, to determine the mechanism by which microglial SIRT1 inhibits NF-?B, we will systematically examine if SIRT1 inhibits NF-?B by deacetylating RelA and/or by reducing RelA phosphorylation in myeloid cells. Using chromatin immunoprecipitation (ChIP) analyses, we will then determine if SIRT1- induced suppression of NF-?B activation involves deacetylation of histones (H3K56Ac) in myeloid cells. Completion of the proposed studies will provide new insight into the molecular mechanisms modulating the microglial loop in neurodegeneration. These studies will also lay the foundation for our long-term goal of developing SIRT1-enhancing strategies as a new therapeutic approach for AD.
This projects aims at investigating mechanisms regulating the proinflammatory responses and microglial toxicity in Alzheimer's disease. This study may provide new therapeutic avenue for treating this devastating disease.
|Martinez-Losa, Magdalena; Tracy, Tara E; Ma, Keran et al. (2018) Nav1.1-Overexpressing Interneuron Transplants Restore Brain Rhythms and Cognition in a Mouse Model of Alzheimer's Disease. Neuron 98:75-89.e5|
|Ward, Michael E; Chen, Robert; Huang, Hsin-Yi et al. (2017) Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis. Sci Transl Med 9:|
|Krabbe, Grietje; Minami, S Sakura; Etchegaray, Jon I et al. (2017) Microglial NF?B-TNF? hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci U S A 114:5029-5034|
|Tracy, Tara E; Gan, Li (2017) Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. Bioessays 39:|
|Wang, Chao; Ward, Michael E; Chen, Robert et al. (2017) Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening. Stem Cell Reports 9:1221-1233|
|Sohn, Peter Dongmin; Tracy, Tara E; Son, Hye-In et al. (2016) Acetylated tau destabilizes the cytoskeleton in the axon initial segment and is mislocalized to the somatodendritic compartment. Mol Neurodegener 11:47|
|Tracy, Tara E; Sohn, Peter Dongmin; Minami, S Sakura et al. (2016) Acetylated Tau Obstructs KIBRA-Mediated Signaling in Synaptic Plasticity and Promotes Tauopathy-Related Memory Loss. Neuron 90:245-60|
|Min, Sang-Won; Chen, Xu; Tracy, Tara E et al. (2015) Critical role of acetylation in tau-mediated neurodegeneration and cognitive deficits. Nat Med 21:1154-62|
|Cho, Seo-Hyun; Chen, Jason A; Sayed, Faten et al. (2015) SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1?. J Neurosci 35:807-18|
|Minami, S Sakura; Shen, Vivian; Le, David et al. (2015) Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with ?7 nicotinic acetylcholine receptor agonists. Biochem Pharmacol 97:454-462|
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