Article

Neuroprotective Sirtuin ratio reversed by ApoE4

The Buck Institute for Research on Aging, Novato, CA 94945.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 10/2013; 110(45). DOI: 10.1073/pnas.1314145110
Source: PubMed

ABSTRACT

The canonical pathogenesis of Alzheimer's disease links the expression of apolipoprotein E ε4 allele (ApoE) to amyloid precursor protein (APP) processing and Aβ peptide accumulation by a set of mechanisms that is incompletely defined. The development of a simple system that focuses not on a single variable but on multiple factors and pathways would be valuable both for dissecting the underlying mechanisms and for identifying candidate therapeutics. Here we show that, although both ApoE3 and ApoE4 associate with APP with nanomolar affinities, only ApoE4 significantly (i) reduces the ratio of soluble amyloid precursor protein alpha (sAPPα) to Aβ; (ii) reduces Sirtuin T1 (SirT1) expression, resulting in markedly differing ratios of neuroprotective SirT1 to neurotoxic SirT2; (iii) triggers Tau phosphorylation and APP phosphorylation; and (iv) induces programmed cell death. We describe a subset of drug candidates that interferes with the APP-ApoE interaction and returns the parameters noted above to normal. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aβ, SirT1:SirT2, APP:phosphorylated (p)-APP, and Tau:p-Tau, is programmatically altered by ApoE4 and offer a simple system for the identification of program mediators and therapeutic candidates.

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    • "Apolipoprotein E 4 allele genotype is a risk factor for accumulation of A 1-42 in the brain related to increased amyloidogenic -and -cleavage of amyloid-protein precursor (APP), and loss of sirtuin T1, and reduced clearance across the bloodbrain barrier. The products of -and -cleavage of APP are the peptides sAPP, A 1-42 , Jcasp, and C31, which cause neurite retraction and cell death [8]. The mechanisms of A 1-42 neurotoxicity [9] involve inflammatory activation, prion-like toxicity, and production of neurofibrillary tangles. "
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