Editors' ChoiceAlzheimer’s Disease

Reducing the UnSIRTainty of Alzheimer’s Disease

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Science Translational Medicine  04 Aug 2010:
Vol. 2, Issue 43, pp. 43ec121
DOI: 10.1126/scitranslmed.3001523

Alzheimer’s disease (AD)—one of the most common causes of dementia—is currently untreatable. Neurofibrillary tangles and β-amyloid plaques, which many believe are neurotoxic, are classic pathological findings in the brains of patients. β-amyloid is generated by cleavage of the amyloid precursor protein (APP) by the β- and γ-secretases in a two-step process. Alternate cleavage of APP by α-secretase (encoded by the ADAM10 gene) and γ-secretase, on the other hand, prevents β-amyloid accumulation. The sirtuins are NAD+-dependent deacetylase proteins that enhance longevity and have neuroprotective properties, but the role of sirtuins in AD and ADAM10 regulation was unknown. New work by Donmez et al. addresses both of these issues.

The authors crossed a mouse model of AD (AD mice) with transgenic mice overexpressing SIRT1, a sirtuin family member, or with mice with a brain-specific knockout of SIRT1. SIRT1-overexpressing AD mice lacked the brain pathology and behavioral deficits seen in AD mice, whereas AD mice in which SIRT1 was knocked out had exacerbations of both of these conditions. SIRT1’s neuroprotection in this model occurred, at least in part, because of deacetylation and activation of the RARβ transcription factor that, in turn, increased expression of the ADAM10 gene. As a result, α-secretase activity increased, which led to alternate APP cleavage products. SIRT1, through activation of ADAM10, also upregulated the Notch signaling pathway, which may have contributed to the observed neuroprotection.

Although these results are intriguing, several questions must be answered before SIRT1 becomes a player in the treatment of this disease. First, is SIRT1 function lost in human AD? Can appropriate sirtuin activators be designed to penetrate the blood-brain barrier? Should they be tested in the treatment of established AD or as preventive agents? However, for the 5.3 million Americans living with AD and their family members, this disease just became a bit less unSIRTain.

G. Donmez et al., SIRT1 suppresses β-amyloid production by activating the α-secretase gene ADAM10. Cell 142, 320–332 (2010). [Abstract]

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