Figure 1.

Aβ accumulation and aggravation under CCH. (I) Non-amyloidogenic pathway: APP is first cleaved by α-secretase to generate sAPPα and C83. C83 then produces P3 and AICD under the action of γ-secretase, which is shifted to the nucleus to regulate Ca²⁺-related gene expression. (II) Amyloidogenic pathway: full-length APP can also be cleaved by BACE1 to release soluble APPβ from the cell membrane and retain C99. Subsequent cleavage of C99 by γ-secretase generates Aβ42/40. (III) CCH-mediated hypoxia can promote BACE1 gene expression by upregulating HIF-1α. (IV) CCH is also likely to increase Aβ accumulation via impairing Aβ clearance. (V) The more aggressive Aβ42 tends to deposit in vulnerable brain regions that are primarily associated with learning and memory. (VI) Aβ40 prefers to deposit in non-neuronal cells, mainly including cerebral vessels.