Amyloid Pathology Is Associated with Progressive Monoaminergic Neurodegeneration in a Transgenic Mouse Model of Alzheimer's Disease

beta-Amyloid (A beta) pathology is an essential pathogenic component in Alzheimer's disease (AD). However, the significance of A beta pathology, including A beta deposits/oligomers and glial reactions, to neurodegeneration is unclear. In particular, despite the A beta neurotoxicity indicated by in vitro studies, mouse models with significant A beta deposition lack robust and progressive loss of forebrain neurons. Such results have fueled the view that A beta 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/PS1 Delta E9 mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain A beta deposition in the APPswe/PS1 Delta E9 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 (similar to 50%) of subcortical MAergic neurons. Degeneration of these neurons occurs without obvious local A beta 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 A beta pathology develops progressive MAergic neurodegeneration occurring in AD cases.