VEGF controls microglial phagocytic response to amyloid-

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