title: Neuroprotective Sirtuin ratio reversed by ApoE4.
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.
authors.affiliation: The Buck Institute for Research on Aging, Novato, CA 94945.
authors.forename: Veena
authors.initials: V
authors.lastname: Theendakara
authors.forename: Alexander
authors.initials: A
authors.lastname: Patent
authors.forename: Clare A
authors.initials: CA
authors.lastname: Peters Libeu
authors.forename: Brittany
authors.initials: B
authors.lastname: Philpot
authors.forename: Sonia
authors.initials: S
authors.lastname: Flores
authors.forename: Olivier
authors.initials: O
authors.lastname: Descamps
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Gabriellee
authors.initials: G
authors.lastname: Cailing
authors.forename: Matthew
authors.initials: M
authors.lastname: Hart
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.forename: Rammohan V
authors.initials: RV
authors.lastname: Rao
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D000544:Alzheimer Disease / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D053318:Apolipoprotein E3 / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000378:metabolism*; D015153:Blotting, Western; D055808:Drug Discovery; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D047468:Immunoprecipitation; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction; D037761:Sirtuins / Q000378:metabolism*; D020349:Surface Plasmon Resonance; D016875:tau Proteins / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D016875:tau Proteins; D037761:Sirtuins