VEGF controls microglial phagocytic response to amyloid-β

Abstract

Microglial cells are well known to be implicated in the pathogenesis of Alzheimer’s disease (AD), due to the impaired clearance of amyloid-β (Aβ) protein. In AD, Aβ 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 Aβ oligomers (Aβo) are the most toxic forms responsible for neuronal and synaptic alterations. Recently, we showed that the Vascular Endothelial Growth Factor (VEGF) counteracts Aβo-induced synaptic alterations and that a peptide derived from VEGF is able to inhibit Aβ aggregation process. Moreover, VEGF has been reported to promote microglial chemotaxis to Aβ brain deposits. We therefore investigated whether VEGF could influence microglial phagocytic response to Aβ, using in vitro and ex vivo models of amyloid accumulation. We report here that VEGF increases Aβo 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 Aβ receptor. Consistently, the soluble form sTREM2 also increases Aβo phagocytosis by microglial cells. Taken together, these findings propose VEGF as a new regulator of Aβ clearance and suggest its potential role in rescuing compromised microglial function in AD.

Decoding sTREM2: its impact on Alzheimer’s disease – a comprehensive review of mechanisms and implications

“…Additionally, BRI2 modulates sTREM2 functionality by inhibiting α-secretase-mediated cleavage of TREM2, affecting microglial phagocytic capabilities under pathological conditions ( Yin T. et al, 2024 ). VEGF is recognized as a pivotal regulator of microglial phagocytosis in AD, facilitating the cleavage and release of sTREM2, thus enhancing the clearance of Aβ oligomers ( de Gea et al, 2023 ). Studies report an age-related increase in CSF sTREM2 levels, suggesting rapid, demand-driven conversion of TREM2 to sTREM2, reflecting a regulatory need or a functional necessity for sTREM2, with the full-length protein serving as its precursor ( Henjum et al, 2016 ).…”

“…Additionally, BRI2 modulates sTREM2 functionality by inhibiting α-secretase-mediated cleavage of TREM2, affecting microglial phagocytic capabilities under pathological conditions . VEGF is recognized as a pivotal regulator of microglial phagocytosis in AD, facilitating the cleavage and release of sTREM2, thus enhancing the clearance of Aβ oligomers (de Gea et al, 2023).…”