Reducing Endogenous α-Synuclein Mitigates the Degeneration of Selective Neuronal Populations in an Alzheimer's Disease Transgenic Mouse Model

Alzheimer's disease (AD) is characterized by the progressive accumulation of amyloid beta (A beta) and microtubule associate protein tau, leading to the selective degeneration of neurons in the neocortex, limbic system, and nucleus basalis, among others. Recent studies have shown that alpha-synuclein (alpha-syn) also accumulates in the brains of patients with AD and interacts with A beta and tau, forming toxic hetero-oligomers. Although the involvement of alpha-syn has been investigated extensively in Lewy body disease, less is known about the role of this synaptic protein in AD. Here, we found that reducing endogenous alpha-syn in an APP transgenic mouse model of AD prevented the degeneration of cholinergic neurons, ameliorated corresponding deficits, and recovered the levels of Rab3a and Rab5 proteins involved in intracellular transport and sorting of nerve growth factor and brain-derived neurotrophic factor. Together, these results suggest that alpha-syn might participate in mechanisms of vulnerability of selected neuronal populations in AD and that reducing alpha-syn might be a potential approach to protecting these populations from the toxic effects of A beta.