Microglial large extracellular vesicles propagate early synaptic dysfunction in Alzheimer's disease

Area of Science:

• Neuroscience
• Cell Biology
• Alzheimer's Disease Research

Background:

• Synaptic dysfunction is an early Alzheimer's disease (AD) hallmark, but its initiation and spread remain unclear.
• Microglial dysfunction and amyloid-beta (Aβ) accumulation are key in AD pathogenesis.

Purpose of the Study:

• To investigate the role of microglial extracellular vesicles (EVs) carrying Aβ in initiating and propagating synaptic dysfunction in Alzheimer's disease.
• To elucidate the mechanism by which Aβ-EVs spread synaptic impairments within neural circuits.

Main Methods:

• In vitro and in vivo studies using mouse models.
• Amyloid-beta extracellular vesicle (Aβ-EV) injection into the mouse entorhinal cortex.
• Assessment of long-term potentiation (LTP) in the entorhinal cortex-dentate gyrus circuitry.
• Optical tweezers and time-lapse imaging to track Aβ-EV-neuron interactions.
• Inhibition of Aβ-EV motility using annexin-V coating.

Main Results:

• Aβ-EVs altered dendritic spine morphology in vitro and impaired synaptic plasticity (LTP) both in vitro and in vivo.
• LTP deficits spread from the entorhinal cortex to the dentate gyrus within 24 hours post-injection.
• Aβ-EVs exhibited anterograde motion along neuronal axons, and inhibiting this motility prevented LTP deficit propagation.
• Neither Aβ42 alone nor non-amyloid inflammatory EVs caused similar propagation of synaptic impairment.

Conclusions:

• Large microglial extracellular vesicles carrying amyloid-beta are implicated in the onset and spread of early synaptic dysfunction in Alzheimer's disease.
• The anterograde motility of Aβ-EVs along neuronal surfaces is a critical mechanism for the propagation of synaptic impairments.
• Targeting Aβ-EVs and their movement presents a novel therapeutic strategy to delay Alzheimer's disease progression.