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

Ying Liu, Mi Jeong Yoo, Alena Savonenko, Wanda Stirling, Donald L. Price, David R. Borchelt, Laura Mamounas, W. Ernest Lyons, Mary E. Blue, Michael K. Lee

Research output: Contribution to journalArticlepeer-review

134 Scopus citations

Abstract

β-Amyloid (Aβ) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of Aβ pathology, including Aβ deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the Aβ neurotoxicity indicated by in vitro studies, mouse models with significant Aβ deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that Aβ 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/PS1ΔE9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Aβ deposition in the APPswe/PS1ΔE9 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 (∼50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local Aβ 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 Aβ pathology develops progressive MAergic neurodegeneration occurring in AD cases.

Original languageEnglish (US)
Pages (from-to)13805-13814
Number of pages10
JournalJournal of Neuroscience
Volume28
Issue number51
DOIs
StatePublished - Dec 17 2008

Keywords

  • Atrophy
  • Axon
  • Aβ-peptide
  • BDNF
  • Neuron death
  • Noradrenergic
  • Serotonergic

Fingerprint Dive into the research topics of 'Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease'. Together they form a unique fingerprint.

Cite this