Proc Natl Acad Sci U S A. 2013 (Nov 5); 110 (45): 18303–8 ~ FULL TEXT
Veena Theendakara, Alexander Patent, Clare A. Peters Libeu, Brittany Philpot, Sonia Flores, Olivier Descamps, Karen S. Poksay, Qiang Zhang, Gabriellee Cailing, Matthew Hart, Varghese John, Rammohan V. Rao, and Dale E. Bredesen
The Buck Institute for Research on Aging,
Novato, CA 94945.
Buck Institute for Research on Aging,
Novato, CA 94945.
This manuscript links ApoE4-mediated signaling with Sirtuin function. Specifically, we show that ApoE4, but not ApoE3, reduces neuroprotective SirT1 levels. Our data support the hypothesis that neuronal connectivity, as reflected in the ratios of critical mediators such as sAPPα:Aβ, SirT1:SirT2, APP:p-APP, and Tau:p-Tau, is programmatically altered by ApoE4. Thus ApoE4, SirT1/2, p-Tau, and p-APP, all may be part of a signaling network that is affected in AD, providing a model for therapeutic candidate screening in AD drug discovery. These findings offer a unique insight into the mechanism by which ApoE4 confers risk for the development of Alzheimer’s disease.
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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