title: Soluble aβ promotes wild-type tau pathology in vivo.
abstract: Growing evidence suggests that soluble Aβ species can drive Alzheimer disease (AD) pathogenesis by inducing a cascade of events including tau hyperphosphorylation, proteasome impairment, and synaptic dysfunction. However, these studies have relied largely on in vitro approaches to examine the role of soluble Aβ in AD. In particular, it remains unknown whether soluble Aβ oligomers can facilitate the development of human wild-type tau pathology in vivo. To address this question, we developed a novel transgenic model that expresses low levels of APP with the Arctic familial AD mutation to enhance soluble Aβ oligomer formation in conjunction with wild-type human tau. Using a genetic approach, we show that reduction of β-site APP cleaving enzyme (BACE) in these ArcTau mice decreases soluble Aβ oligomers, rescues cognition, and, more importantly, reduces tau accumulation and phosphorylation. Notably, BACE reduction decreases the postsynaptic mislocalization of tau in ArcTau mice and reduces the association between NMDA receptors and PSD-95. These studies provide critical in vivo evidence for a strong mechanistic link between soluble Aβ, wild-type tau, and synaptic pathology.
authors.affiliation: Department of Neurobiology and Behavior, Institute for Memory Impairment and Neurological Disorders, and Sue and Bill Gross Stem Cell Research Center, University of California Irvine, Irvine, California 92697, USA.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Chabrier
authors.forename: Mathew
authors.initials: M
authors.lastname: Blurton-Jones
authors.forename: Andranik A
authors.initials: AA
authors.lastname: Agazaryan
authors.forename: Joy L
authors.initials: JL
authors.lastname: Nerhus
authors.forename: Hilda
authors.initials: H
authors.lastname: Martinez-Coria
authors.forename: Frank M
authors.initials: FM
authors.lastname: LaFerla
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D007858:Learning / Q000502:physiology*; D008568:Memory / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins