Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease

J Neurosci. 2008 Dec 17;28(51):13805-14. doi: 10.1523/JNEUROSCI.4218-08.2008.


beta-Amyloid (Abeta) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of Abeta pathology, including Abeta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Abeta neurotoxicity indicated by in vitro studies, mouse models with significant Abeta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Abeta pathology is insufficient for neurodegeneration in vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether the APPswe/PS1DeltaE9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Abeta deposition in the APPswe/PS1DeltaE9 model is associated with progressive losses of the forebrain MAergic afferents. Significantly, axonal degeneration is associated with significant atrophy of cell bodies and eventually leads to robust loss (approximately 50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local Abeta or tau pathology at the subcortical sites and precedes the onset of anxiety-associated behavior in the mice. Our results show that a transgenic mouse model of Abeta pathology develops progressive MAergic neurodegeneration occurring in AD cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / genetics
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Biogenic Monoamines / metabolism*
  • Brain Stem / metabolism
  • Brain Stem / pathology
  • Disease Models, Animal
  • Disease Progression
  • Mesencephalon / metabolism
  • Mesencephalon / pathology
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / complications
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology*
  • Neurons, Afferent / metabolism
  • Neurons, Afferent / pathology*
  • Prosencephalon / metabolism
  • Prosencephalon / pathology*


  • Amyloid beta-Peptides
  • Biogenic Monoamines