Amyloid pathology is associated with progressive monoaminergic neurodegeneration in a transgenic mouse model of Alzheimer's disease.
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.
Liu
Ying
Y
Department of Pathology, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Yoo
Mi-Jeong
MJ
Savonenko
Alena
A
Stirling
Wanda
W
Price
Donald L
DL
Borchelt
David R
DR
Mamounas
Laura
L
Lyons
W Ernest
WE
Blue
Mary E
ME
Lee
Michael K
MK
D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D001933:Brain Stem / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D008636:Mesencephalon / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology*; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology*
D016229:Amyloid beta-Peptides; D015306:Biogenic Monoamines