Fig. 7. (A-E) Proposed models of AV accumulation leading to elevated A levels. (A) Usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV build up are expected to promote A generation and accumulation. (B,C) These conditions include impaired and delayed maturation of autophagosomes to (B) lysosomes or (C) acute induction of autophagy. (D,E) Within neurons, AVs normally mature to lysosomes efficiently as they reach the perikaryon and are usually rare (D). In AD, however, AVs in neurites fail to mature completely to lysosomes either as a cause or consequence of disrupted proteolytic clearance and/or retrograde transport of AVs, thereby promoting the accumulation of AVs capable of generating A and the delayed degradation of A by lysosomes (E). The continued capacity of immature AVs to fuse with other membranous structures, including possibly the plasma membrane, is a possible basis for slow exocytic release of AV contents, including A, from the dystrophic neurite.