title: Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease.
abstract: A central issue in the pathogenesis of tauopathy is the question of how tau protein dysfunction leads to neurodegeneration. We have previously demonstrated that the absence of tau protein is associated with destabilization of microtubules and impaired neurite outgrowth (Dawson et al., 2001; Rapoport et al., 2002). We now hypothesize that the absence of functional tau protein may render the central nervous system more vulnerable to secondary insults such as the overexpression of mutated beta amyloid precursor protein (APP) and traumatic brain injury. We therefore crossed tau knockout mice (Dawson et al., 2001) to mice overexpressing a mutated human APP (APP(670,671), A(sw)) (Hsiao et al., 1996) and created a mouse model (A(sw)/mTau(-/-)) that provides evidence that the loss of tau function causes degeneration of neuronal processes. The overexpression of APP(670,671) in tau knockout mice, elicits the extensive formation of axonal spheroids. While spheroids are only found associated with Abeta plaques in mice expressing APP(670,671) on an endogenous mouse tau background (Irizarry et al., 1997), A(sw)/mTau(-/-) mice have spheroids not only surrounding Abeta plaques but also in white matter tracks and in the neuropil. Plaque associated and neuropil dystrophic neurites and spheroids are prominent features of Alzheimer's disease (Masliah et al., 1993; Terry, 1996; Stokin et al., 2005), and our current data suggests that loss of tau function may lead to neurodegeneration.
authors.affiliation: Division of Neurology, Duke University, Durham, NC 27710, USA. dawso009@mc.duke.edu
authors.forename: H N
authors.initials: HN
authors.lastname: Dawson
authors.forename: V
authors.initials: V
authors.lastname: Cantillana
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.forename: M P
authors.initials: MP
authors.lastname: Vitek
authors.forename: D M
authors.initials: DM
authors.lastname: Wilcock
authors.forename: J R
authors.initials: JR
authors.lastname: Lynch
authors.forename: D T
authors.initials: DT
authors.lastname: Laskowitz
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000276:immunology / Q000633:toxicity; D000818:Animals; D001259:Ataxia / Q000209:etiology; D001369:Axons / Q000473:pathology*; D001930:Brain Injuries / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D007114:Immunization; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009410:Nerve Degeneration / Q000473:pathology*; D016501:Neurites / Q000648:ultrastructure; D019581:Neuropil / Q000648:ultrastructure; D058225:Plaque, Amyloid / Q000648:ultrastructure; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000633:toxicity; D016875:tau Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D011993:Recombinant Fusion Proteins; D016875:tau Proteins