Figure 7.

Schematic representations of potential mechanisms of Mfsd2a and Aqp4 actions at the BRB in AD and during aging. (A) In the normally functioning BRB, Mfsd2a-mediated DHA transport inhibits the formation of caveolae possibly through the inhibition of srebp1-c. In AD and aging, Mfsd2a downregulation, associated with the loss of pericytes, lessens the inhibition of the formation of caveolae, leading to increased vesicle transport through BRB, leaky barrier, and Aβ accumulation. In AD, the upregulation of srebp1-c and the downregulation of Lxrβ and Hmgcr could potentiate Mfsd2a downregulation. (B) Aqp4 expression is polarized, as it is densely expressed by astrocytes almost exclusively at the end feet, in direct contact with the perivascular space. In aging and in AD, Aap4 polarization is diminished. The loss of Aqp4 polarization is associated with increased Aβ accumulation.