β-Amyloid peptides enhance α-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of beta -amyloid and alpha -synuclein, respectively. Some patients have clinical and pathological features of both diseases, raising the possibility of overlapping pathogenetic pathways. We generated transgenic (tg) mice with neuronal expression of human beta -amyloid peptides, alpha -synuclein, or both. The functional and morphological alterations in doubly tg mice resembled the Lewy-body variant of Alzheimer's disease. These mice had severe deficits in learning and memory, developed motor deficits before alpha -synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more alpha -synuclein-immunoreactive neuronal inclusions than a-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in a-synuclein singly tg mice. beta -Amyloid peptides promoted aggregation of a-synuclein in a cell-free system and intraneuronal accumulation of a-synuclein in cell culture. P-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of alpha -synuclein and exacerbating alpha -synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of beta -amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.