title: Soluble α-synuclein is a novel modulator of Alzheimer's disease pathophysiology.
abstract: Recent evidence has emphasized soluble species of amyloid-β (Aβ) and tau as pathogenic effectors in Alzheimer's disease (AD). Despite the fact that Aβ, tau, and α-synuclein (αSyn) can promote each other's aggregation, the potential contribution of soluble αSyn to AD pathogenesis is unknown. Here, we found an approximate twofold increase over controls in soluble αSyn levels in AD brains in the absence of Lewy body cytopathology. Importantly, soluble αSyn levels were a quantitatively stronger correlate of cognitive impairment than soluble Aβ and tau levels. To examine a putative role for αSyn in modulating cognitive function, we used the Barnes circular maze to assess spatial reference memory in transgenic mice overexpressing human wild-type αSyn. The results revealed that an approximate threefold elevation of αSyn in vivo induced memory deficits similar to those observed in AD mouse models. The neurobiological changes associated with this elevation of soluble αSyn included decreases in selected synaptic vesicle proteins and an alteration of the protein composition of synaptic vesicles. Finally, a synergism between Aβ/APP and human tau seems to be responsible for the abnormal elevation of soluble αSyn in transgenic mice. Altogether, our data reveal an unexpected role for soluble, intraneuronal αSyn in AD pathophysiology.
authors: Department of Neuroscience, N. Bud Grossman Center for Memory Research and Care, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55414, USA.
authors: Megan E
authors: ME
authors: Larson
authors: Mathew A
authors: MA
authors: Sherman
authors: Susan
authors: S
authors: Greimel
authors: Michael
authors: M
authors: Kuskowski
authors: Julie A
authors: JA
authors: Schneider
authors: David A
authors: DA
authors: Bennett
authors: Sylvain E
authors: SE
authors: Lesné
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D060825:Cognitive Dysfunction / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D018782:Maze Learning; D051379:Mice; D008822:Mice, Transgenic; D036421:Nerve Fibers, Unmyelinated / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009483:Neuropsychological Tests; D053764:Presenilin-1 / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053764:Presenilin-1; D051844:alpha-Synuclein; D016875:tau Proteins