ABSTRACT
Microglial cells are well known to be implicated in the pathogenesis of Alzheimer's disease (AD), due to the impaired clearance of amyloid-ß (Aß) protein. In AD, Aß accumulates in the brain parenchyma as soluble oligomers and protofibrils, and its aggregation process further give rise to amyloid plaques. Compelling evidence now indicate that Aß oligomers (Aßo) are the most toxic forms responsible for neuronal and synaptic alterations. Recently, we showed that the Vascular Endothelial Growth Factor (VEGF) counteracts Aßo-induced synaptic alterations and that a peptide derived from VEGF is able to inhibit Aß aggregation process. Moreover, VEGF has been reported to promote microglial chemotaxis to Aß brain deposits. We therefore investigated whether VEGF could influence microglial phagocytic response to Aß, using in vitro and ex vivo models of amyloid accumulation. We report here that VEGF increases Aßo phagocytosis by microglial cells and further characterized the molecular basis of the VEGF effect. VEGF is able to control α-secretase activity in microglial cells, resulting in the increased cleavage of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2), a major microglial Aß receptor. Consistently, the soluble form sTREM2 also increases Aßo phagocytosis by microglial cells. Taken together, these findings propose VEGF as a new regulator of Aß clearance and suggest its potential role in rescuing compromised microglial function in AD.
