Figure 7

Schematic illustration of a hypothetic model for BACE1 elevation in vascular and brain-specific cellular elements in angiopathic (panel A) and leptomeningeal (panel B) amyloidosis. Arteriolar profile is used here to construct the model to show the major relevant cellular components and pathological events. BACE1 elevation first occurs in endothelial cells (EC), resulting in Aβ rise and aggregation in the smooth muscle cell (SMC) layer. This is followed by the damage of tight junctions (TJ) and blood brain barrier, causing leakage of blood contents into the SMC layer (curved arrows). The Aβ products and/or blood infiltration then induce SMC degeneration, and further a reactive response of the perivascular axonal terminals, manifested as aberrant sprouting and dystrophy. The invasion of the Aβ producing dystrophic neurites into the vascular wall leads to a vicious cycle of amyloidosis, cell degeneration and microbleeding. This process may end up with a “burnout” stage whereby the ECs, SMCs and dystrophic neurites all degenerate (panel A). For leptomeningeal amyloidosis, we propose that the initial events (endothelial Aβ overproduction, Aβ aggregation, BBB breakdown, and SMC degeneration) potentiate BACE1 expression in the nearby meningeal cells. A vicious cycle of pathogenesis in the blood vessel and meninge collectively contribute to the spread of amyloidosis along the leptomeninge (panel B).