TY - JOUR
T1 - Neuroprotective Sirtuin ratio reversed by ApoE4
AU - Theendakara, Veena
AU - Patent, Alexander
AU - Libeu, Clare A.Peters
AU - Philpot, Brittany
AU - Flores, Sonia
AU - Descamps, Olivier
AU - Poksay, Karen S.
AU - Zhang, Qiang
AU - Cailing, Gabriellee
AU - Hart, Matthew
AU - John, Varghese
AU - Rao, Rammohan V.
AU - Bredesen, Dale E.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2013/11/5
Y1 - 2013/11/5
N2 - 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 (sAPPa) 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 sAPPa: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.
AB - 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 (sAPPa) 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 sAPPa: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.
UR - http://www.scopus.com/inward/record.url?scp=84887314994&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887314994&partnerID=8YFLogxK
U2 - 10.1073/pnas.1314145110
DO - 10.1073/pnas.1314145110
M3 - Article
C2 - 24145446
AN - SCOPUS:84887314994
VL - 110
SP - 18303
EP - 18308
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 45
ER -