Fig. 2

Transportation of peripheral pathological proteins into the brain. Peripheral pathological proteins can enter the brain through various pathways. Aβ, Tau, and α-syn enriched in the gastrointestinal tract can be transported via the vagus nerve. On the other hand, these pathological proteins can flow through the bloodstream from the periphery into the CNS. When the BBB remains intact, these proteins can cross into the CNS through specific transporters, such as AGER, which selectively transports Aβ. Additionally, EVs carrying these pathological proteins can be endocytosed by brain microvascular endothelial cells, allowing them to cross the BBB. When the BBB is compromised, these pathological proteins, whether in free form or encapsulated within EVs, can infiltrate the brain through the intercellular spaces