Fig. 2.

Overview of the impact of Aβ, Tau and α-syn on ECs, brain macrophages and pericytes. Aβ oligomers and fibrils can enter in ECs producing their activation and damaging TJPs eventually resulting in ECs death. While extracellular Tau fibrillary aggregates can damage TJPs, Tau oligomers can also enter ECs and induce their activation that in turn can produce ECs senescence, thus altering vessel morphology and causing blood flow stalling. ECs can uptake α-syn fibrils and oligomers that can interfere with ECs function, including VWF release. Extracellular Aβ, Tau and α-syn fibrillary aggregates and oligomers have been found to activate brain macrophages mainly by acting as DAMPs. Intracellular Tau aggregates can also produce a peculiar neuronal pro-inflammatory phenotype with Phosphatidylserine (PtdSer) membrane exposure that stimulates their phagocytosis by microglial cells, which consequently become hypofunctional. Brain macrophage activation induced by Aβ, Tau, and α-syn leads to oxidative stress, generating reactive oxygen species (ROS) and producing pro-inflammatory cytokines. This cascade of events subsequently impacts ECs, contributing to compromised BBB integrity. Additionally, pro-inflammatory cytokines derived from activated brain macrophages and ECs may stimulate ECs expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), thus attracting leukocyte adhesion from circulation. Aβ, Tau and α-syn can also differentially affect pericytes. Aβ can induce pericyte degeneration with subsequent loss of vascular support. Aβ also stimulates pericyte contraction by promoting endothelin release, thus impacting CBF. Tau monomers can enter pericytes stimulating their activation and dysfunction following repeated head trauma. Pericytes can be activated by extracellular α-syn aggregates accumulation and by the uptake of high levels of monomeric α-syn, which can then be transmitted between pericytes through tunnelling nanotubes (TNTs). In turn, pericytes can become hypofunctional and there is a loss of their trophic support on ECs