• Alzheimer
• microglia
• vesicles
• hippocampus
• network

A major neuropathological hallmark of Alzheimer’s disease (AD) is the accumulation of extracellular amyloid-beta (Aβ). Extensive literature implicates Aβ-dependent synaptic dysfunction as an early mechanism affected in AD, that propagates from the Entorhinal Cortex (EC) to connected regions, such as the hippocampus and leading to an aberrant network activity. However, how synaptic dysfunction starts, propagates and causes network alteration is not yet clear. Recent evidence suggests that extracellular vesicles (EVs) secreted from microglia may facilitate trans-synaptic delivery of pathogenic proteins, including Aβ, over large distances. To test the effect of EVs carrying Aβ along the EC-hippocampal connections we performed in vivo chronic EEG recording in freely moving mice, injected in the lateral EC (LEC) with vehicle, Aβ-EVs, Aβ [1-42], ctrl-EVs or Aβ-EVs + Annexin V (which reduces EVs movement).The results confirmed that Aβ-EVs induced a network dysfunction characterized by increased cortico-hippocampal excitability and the presence of spike-wave discharges, a typical feature of absence epilepsy and early AD. All these effects were reduced by Annexin V vesicles pre-treatment suggesting that Aβ-EVs movement contributes to the disruption of cortico-hippocampal network activity and memory impairment. Our model proposes a new biological mechanism for the spreading of Aβ pathology and offers the opportunity to test treatments targeting the early stage of the disease.