Activated microglial exosomes enhance α-Synuclein internalization and accelerate neurodegeneration in lewy body dementia

Lewy body dementia (LBD), which includes Parkinson's disease dementia and dementia with Lewy bodies, is characterized by progressive cognitive decline, α-synuclein (α-Syn) aggregation, and concurrent microglial activation and neuroinflammation. The nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input, plays a key role in cognitive function and is particularly affected in LBD. Cholinergic neurons within the NBM are highly vulnerable to Lewy body pathology, yet the underlying mechanisms remain poorly understood. In this study, we employed a mouse model with PFF injections into the NBM to investigate how microglia and their exosomes influence α-Syn pathology. We found that exosomes derived from activated microglia exacerbate α-Syn deposition and cognitive deficits, whereas microglial depletion mitigates these pathological changes. In vitro, activated microglial exosomes enhanced the uptake of exogenous α-Syn by cholinergic neurons. Mechanistically, we discovered that microglial exosomes can transfer bioactive membrane receptors to neurons. Focusing on lymphocyte-activation gene 3 (LAG3), a receptor critical for α-Syn internalization, we demonstrated that LAG3 is abundant in exosomes from activated-but not resting-microglia. These exosomes deliver LAG3 to neuronal membranes via an endosomal recycling pathway, a process facilitated by elevated cholesterol content, thereby promoting α-Syn uptake. Together, these findings indicate that microglial exosomes function not only as carriers of signaling molecules but also as vectors for receptor transfer, reshaping neuronal membrane composition. Our results provide a mechanistic explanation for the heightened vulnerability of NBM cholinergic neurons in LBD and reveal a novel pathway in which LAG3-rich microglial exosomes drive neuronal α-Syn internalization, advancing our understanding of neurodegeneration and identifying potential therapeutic targets.