title: Accumulation of pathological tau species and memory loss in a conditional model of tauopathy.
abstract: Neurofibrillary tangles (NFTs) are a pathological hallmark of Alzheimer's disease and other tauopathies, but recent studies in a conditional mouse model of tauopathy (rTg4510) have suggested that NFT formation can be dissociated from memory loss and neurodegeneration. This suggests that NFTs are not the major neurotoxic tau species, at least during the early stages of pathogenesis. To identify other neurotoxic tau protein species, we performed biochemical analyses on brain tissues from the rTg4510 mouse model and then correlated the levels of these tau proteins with memory loss. We describe the identification and characterization of two forms of tau multimers (140 and 170 kDa), whose molecular weight suggests an oligomeric aggregate, that accumulate early in the pathogenic cascade in this mouse model. Similar tau multimers were detected in a second mouse model of tauopathy (JNPL3) and in tissue from patients with Alzheimer's disease and FTDP-17 (frontotemporal dementia and parkinsonism linked to chromosome 17). Moreover, levels of the tau multimers correlated consistently with memory loss at various ages in the rTg4510 mouse model. Our findings suggest that accumulation of early-stage aggregated tau species, before the formation of NFT, is associated with the development of functional deficits during the pathogenic progression of tauopathy.
authors.affiliation: Mayo Clinic Jacksonville, Jacksonville, Florida 32224, USA.
authors.forename: Zdenek
authors.initials: Z
authors.lastname: Berger
authors.forename: Hanno
authors.initials: H
authors.lastname: Roder
authors.forename: Amanda
authors.initials: A
authors.lastname: Hanna
authors.forename: Aaron
authors.initials: A
authors.lastname: Carlson
authors.forename: Vijayaraghavan
authors.initials: V
authors.lastname: Rangachari
authors.forename: Mei
authors.initials: M
authors.lastname: Yue
authors.forename: Zbigniew
authors.initials: Z
authors.lastname: Wszolek
authors.forename: Karen
authors.initials: K
authors.lastname: Ashe
authors.forename: Joshua
authors.initials: J
authors.lastname: Knight
authors.forename: Dennis
authors.initials: D
authors.lastname: Dickson
authors.forename: Cathy
authors.initials: C
authors.lastname: Andorfer
authors.forename: Terrone L
authors.initials: TL
authors.lastname: Rosenberry
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Christopher
authors.initials: C
authors.lastname: Janus
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D016875:tau Proteins