S3‐02‐02: Sirtuin signaling in Alzheimer's disease

Aging is the predominant and unifying risk factor for neurodegenerative diseases, including Alzheimer's disease (AD), the most common dementia in the elderly. SIRT1, a member of sirtuin family of histone deacetylases, supports and promotes longevity in diverse organisms and can extend lifespan when upregulated. In AD brains, SIRT1 levels are significantly lower than in nondemented controls and correlate negatively with the Braak stages of the disease. To determine how SIRT1 protects against neurodegeneration in AD, we used primary cortical cultures and transgenic mice that overexpress familial AD-mutant human amyloid precursor protein (hAPP) in neurons and have high levels of amyloid beta (Abeta) in the brain. Additional genetic manipulations are achieved with Lentiviral vectors or by cross breeding with knockout mice. One of the main nonhistone substrates of SIRT1 is NF-kappa B, a key activator of inflammatory responses that have been implicated in neurodegeneration. In cultured microglia, SIRT1 activation protected against Abeta toxicity by inhibiting NF-kappa B signaling. Consistent with the observation that SIRT1 levels are reduced in AD patients, treatment with oligomeric Abeta markedly reduced SIRT1 protein and mRNA levels in microglial cultures. However, activation of the fractalkine receptor (CX3CR1), a microglia-specific chemokine receptor induced by binding to its exclusive ligand (CX3CL1) prevented the Abeta-induced SIRT1 downregulation seen in cultured microglia. In contrast, deletion of CX3CR1 in hAPP mice significantly increased the expression of inflammatory mediators and exacerbated amyloid beta-related neuronal deficits. These observations suggest that deficient CX3CR1 signaling could depress SIRT1 levels in microglia, leading to chronic NF-kappa B activation and microglial toxicity. Activation of sirtuin signaling pathways has diverse anti-aging effects and may provide new therapeutic avenues for preventing or delaying age-related ailments, including AD.