A(beta) generation in autophagic vacuoles

Abstract

Alzheimer's disease (AD) is the most common form of dementia among older people. It is characterized by the extracellular accumulation of beta-amyloid (Abeta) deposits called senile or neuritic plaques. Abeta is generated by the proteolytic cleavage of Abeta precursor protein (APP) by beta and gamma-secretases localized in the secretory and endocytic compartments. In this issue, Yu et al. (on p. 87) report a novel mechanism for the generation of Abeta peptides, which takes place in autophagic vacuoles (AVs) that accumulate in AD brains.

Figure 1.

Aβ production in AVs. The membrane dynamics of autophagy and its proposed role in Aβ generation in the AD brain are depicted. A portion of cytoplasm is enclosed by the isolation membrane to form an autophagosome. The outer membrane of the autophagosome then fuses with a lysosome to degrade the inside materials. Organelles can be degraded by this pathway. After digestion is completed, autolysosomes are thought to become dense lysosomes. The origin of the isolation membrane is not known, but vesicles might be delivered from the ER. Thus, APP and the γ-secretase complex could be incorporated into the autophagosome membrane. Alternatively, ER and the Golgi apparatus containing APP and the γ-secretase complex may be engulfed by autophagosomes. In AD, some steps of autophagosome/autolysosome maturation are blocked, which may promote Aβ production.