Principal Investigators

    GAN, LI



    Contact information of lead PI



    Title of project or programme

    SIRT1 Limits Microglial Toxicity in Alzheimers Disease

    Source of funding information

    NIH (NIA)

    Total sum awarded (Euro)

    € 1,838,774.31

    Start date of award


    Total duration of award in years


    The project/programme is most relevant to:

    Alzheimer's disease & other dementias


    Acquired Cognitive Impairment... Aging... Alzheimer's Disease... Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD)... Brain Disorders... Dementia... Genetics... Immune System... Neurodegenerative... Neurosciences

    Research Abstract

    DESCRIPTION (provided by applicant): 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 (Aß) 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 Aß toxicity. Inhibition of NF-?B by SIRT1, a member of the sirtuin family of histone deacetylases, protected against microglia toxicity in Aß-treated primary cultures. In AD brains, SIRT1 levels were markedly reduced. SIRT1 expression in cultured microglia was significantly diminished by Aß 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 Aß-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 Aß-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 Aß-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.

    Lay Summary

    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.

    Further information available at:

Types: Investments > €500k
Member States: United States of America
Diseases: Alzheimer's disease & other dementias
Years: 2016
Database Categories: N/A
Database Tags: N/A

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