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

TLDR

Alzheimer’s and Parkinson’s diseases involve cerebral β‑amyloid and α‑synuclein accumulation, and some patients exhibit overlapping clinical and pathological features, suggesting shared pathogenic pathways. The study used transgenic mice expressing human β‑amyloid peptides, α‑synuclein, or both in neurons. Doubly transgenic mice displayed Lewy‑body–like pathology, severe cognitive and motor deficits, increased α‑synuclein inclusions (fibrillar), and age‑dependent cholinergic degeneration, indicating that β‑amyloid promotes α‑synuclein aggregation and exacerbates neurodegeneration, suggesting that β‑amyloid‑targeted therapies could benefit a broader spectrum of disorders.

Abstract

Alzheimer's disease and Parkinson's disease are associated with the cerebral accumulation of β-amyloid and α-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 β-amyloid peptides, α-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 α-synuclein singly tg mice, and showed prominent age-dependent degeneration of cholinergic neurons and presynaptic terminals. They also had more α-synuclein-immunoreactive neuronal inclusions than α-synuclein singly tg mice. Ultrastructurally, some of these inclusions were fibrillar in doubly tg mice, whereas all inclusions were amorphous in α-synuclein singly tg mice. β-Amyloid peptides promoted aggregation of α-synuclein in a cell-free system and intraneuronal accumulation of α-synuclein in cell culture. β-Amyloid peptides may contribute to the development of Lewy-body diseases by promoting the aggregation of α-synuclein and exacerbating α-synuclein-dependent neuronal pathologies. Therefore, treatments that block the production or accumulation of β-amyloid peptides could benefit a broader spectrum of disorders than previously anticipated.