Limits...
A(beta) generation in autophagic vacuoles.

Mizushima N - J. Cell Biol. (2005)

Bottom Line: Alzheimer's disease (AD) is the most common form of dementia among older people.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan. nmizu@rinshoken.or.jp

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.

Show MeSH

Related in: MedlinePlus

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.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2171221&req=5

fig1: 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.

Mentions: Autophagy is a generic term for pathways that transport cytosolic contents to lysosomes. Three types of autophagy have been proposed: macroautophagy, microautophagy, and chaperone-mediated autophagy (Cuervo, 2004; Levine and Klionsky, 2004). Among these, macroautophagy is believed to be responsible for the majority of intracellular protein degradation. When macroautophagy (hereafter simply referred to as autophagy) is induced by nutrient starvation and other stresses or chemical agents, cytoplasmic constituents, including organelles, are enclosed by membrane cisternae known as isolation membranes (Fig. 1). Closure of these membranes results in the formation of double membrane structures called autophagosomes. The autophagosomes eventually fuse with lysosomes to become autolysosomes. Lysosomal hydrolases degrade the cytoplasm-derived contents of the autophagosome together with its inner membrane. The primary role of autophagy is adaptation to nutrient starvation; autophagy is extensively induced after food withdrawal (Mizushima et al., 2004) and during the early neonatal period (Kuma et al., 2004). Besides this fundamental role, autophagy plays pleiotropic roles in intracellular clearance, degradation of invading bacteria, antigen presentation, and possibly cell death (Debnath et al., 2005). In addition, the relationship of autophagy to various diseases is now attracting attention.


A(beta) generation in autophagic vacuoles.

Mizushima N - J. Cell Biol. (2005)

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.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171221&req=5

fig1: 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.
Mentions: Autophagy is a generic term for pathways that transport cytosolic contents to lysosomes. Three types of autophagy have been proposed: macroautophagy, microautophagy, and chaperone-mediated autophagy (Cuervo, 2004; Levine and Klionsky, 2004). Among these, macroautophagy is believed to be responsible for the majority of intracellular protein degradation. When macroautophagy (hereafter simply referred to as autophagy) is induced by nutrient starvation and other stresses or chemical agents, cytoplasmic constituents, including organelles, are enclosed by membrane cisternae known as isolation membranes (Fig. 1). Closure of these membranes results in the formation of double membrane structures called autophagosomes. The autophagosomes eventually fuse with lysosomes to become autolysosomes. Lysosomal hydrolases degrade the cytoplasm-derived contents of the autophagosome together with its inner membrane. The primary role of autophagy is adaptation to nutrient starvation; autophagy is extensively induced after food withdrawal (Mizushima et al., 2004) and during the early neonatal period (Kuma et al., 2004). Besides this fundamental role, autophagy plays pleiotropic roles in intracellular clearance, degradation of invading bacteria, antigen presentation, and possibly cell death (Debnath et al., 2005). In addition, the relationship of autophagy to various diseases is now attracting attention.

Bottom Line: Alzheimer's disease (AD) is the most common form of dementia among older people.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioregulation and Metabolism, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan. nmizu@rinshoken.or.jp

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.

Show MeSH
Related in: MedlinePlus