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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG036884-02
Application #
8517531
Study Section
Cellular and Molecular Biology of Glia Study Section (CMBG)
Program Officer
Petanceska, Suzana
Project Start
2012-08-01
Project End
2017-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$385,358
Indirect Cost
$183,600
Name
J. David Gladstone Institutes
Department
Type
DUNS #
099992430
City
San Francisco
State
CA
Country
United States
Zip Code
94158
Minami, S Sakura; Min, Sang-Won; Krabbe, Grietje et al. (2014) Progranulin protects against amyloid ? deposition and toxicity in Alzheimer's disease mouse models. Nat Med 20:1157-64
Grinberg, Lea Tenenholz; Wang, Xuehua; Wang, Chao et al. (2013) Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation. Acta Neuropathol 125:581-93