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Neuroprotective Sirtuin ratio reversed by ApoE4
Journal article   Open access   Peer reviewed

Neuroprotective Sirtuin ratio reversed by ApoE4

Veena Theendakara, Alexander Patent, Clare Peters Libeu, Brittany Philpot, Sonia Flores, Olivier Descamps, Karen S Poksay, Qiang Zhang, Gabriellee Cailing, Matthew Hart, …
Proceedings of the National Academy of Sciences - PNAS, Vol.110(45), pp.18303-18308
11/05/2013
DOI: 10.1073/pnas.1314145110
PMCID: PMC3831497
PMID: 24145446
url
https://doi.org/10.1073/pnas.1314145110View
Published (Version of record) Open Access

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.
 Biological Sciences

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