Calorie Restriction May Prevent Alzheimer's

[Guest guest]

A simpler description of the following abstract can be found at:

www.sciencedaily.com/releases/2006/06/060614113128.htm

--Thin Man

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J Biol Chem. 2006 Jun 2; [Epub ahead of print]

Neuronal SIRT1 activation as a novel mechanism underlying the prevention of

Alzheimer's

disease amyloid neuropathology by calorie restriction.

Qin W, Yang T, Ho L, Zhao Z, Wang J, Chen L, Thiyagarajan M, Macgrogan D,

Rodgers JT,

Puigserver P, Sadoshima J, Deng H H, Pedrini S, Gandy S, Sauve A, Pasinetti GM.

Psychiatry, Mount Sinai School of Medicine, New York, NY 10029.

Nicotinamide adenine dinucleotide (NAD)+®-dependent sirtuins have been

identified to

be key regulators in the lifespan extending effects of calorie restriction (CR)

in a number

of species. In this study we report for the first time that promotion of the

NAD+®-

dependent sirtuin, SIRT1 mediated deacetylase activity, may be a mechanism by

which CR

influences Alzheimer's disease (AD)-type amyloid neuropathology. Most

importantly, we

report that the predicted attenuation of beta-amyloid (Abeta) content in the

brain during

CR can be reproduced in mouse neurons in vitro by manipulating cellular SIRT1

expression/activity through mechanisms involving the regulation of the

serine/threonine

Rho kinase ROCK1, known in part, for its role in the inhibition of the

non-amyloidogenic

alpha-secretase processing of the amyloid precursor protein (APP). Conversely,

we found

that the expression of constitutively active ROCK1 in vitro cultures

significantly prevented

SIRT1 mediated response, suggesting that alpha-secretase activity is required

for SIRT1

mediated prevention of AD-type amyloid neuropathology. Consistently we found

that the

expression of exogenous human (h)SIRT1 in the brain of hSIRT1 transgenics also

resulted

in decreased ROCK1 expression and elevated alpha-secretase activity in vivo.

These

results demonstrate for the first time a role for SIRT1 activation in the brain

as a novel

mechanism through which CR may influence AD amyloid neuropathology. The study

provides a potentially novel pharmacological strategy for AD prevention and/or

treatment.

PMID: 16751189 [PubMed - as supplied by publisher]