Loss of tau elicits axonal degeneration in a mouse model of Alzheimer's disease

H. N. Dawson, V. Cantillana, M. Jansen, H. Wang, M. P. Vitek, D. M. Wilcock, J. R. Lynch, D. T. Laskowitz

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

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 (APP670,671, Asw) (Hsiao et al., 1996) and created a mouse model (Asw/mTau-/-) that provides evidence that the loss of tau function causes degeneration of neuronal processes. The overexpression of APP670,671 in tau knockout mice, elicits the extensive formation of axonal spheroids. While spheroids are only found associated with Aβ plaques in mice expressing APP670,671 on an endogenous mouse tau background (Irizarry et al., 1997), Asw/mTau-/- mice have spheroids not only surrounding Aβ 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.

Original languageEnglish
Pages (from-to)516-531
Number of pages16
JournalNeuroscience
Volume169
Issue number1
DOIs
StatePublished - Aug 2010

Bibliographical note

Funding Information:
This work was supported in part by Alzheimer's Association Grant IIRG-02-4160 HND, Institute for Study of Aging/ADDF 261102.01 DTL and NIH K08-AG22230-03 JRL. We thank Dr. Anyang Sun for providing his expertise in axonal degeneration. We thank Dr. Van Nostram's laboratory for performing the Aβ elisa.

Keywords

  • APP
  • Axonal degeneration
  • Head injury
  • Immunization
  • Spheroids
  • Tau

ASJC Scopus subject areas

  • General Neuroscience

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