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

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 byin vitrostudies, 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 neurodegenerationin vivo. In this study, because monoaminergic (MAergic) neurons show degenerative changes at early stages of AD, we examined whether theAPPswe/PS1ΔE9mouse model recapitulates progressive MAergic neurodegeneration occurring in AD cases. We show that the progression forebrain Aβ deposition in theAPPswe/PS1ΔE9model 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.