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Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.

Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA - J. Cell Biol. (2005)

Bottom Line: Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity.Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production.Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

View Article: PubMed Central - PubMed

Affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.

ABSTRACT
Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

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Related in: MedlinePlus

Proposed models of AV accumulation leading to elevated Aβ levels. The schematic of macroautophagy depicts (A) the usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV buildup (B and C) are expected to promote Aβ generation and accumulation, including impaired or delayed maturation of autophagosomes to lysosomes (B) or acute maximum induction of macroautophagy (C). Within neurons, AVs normally progress to lysosomes efficiently and are rarely seen in neurons (D). In AD, the disrupted retrograde transport of AVs in dendrites represents one of several possible mechanisms that impede the maturation of AVs to lysosomes, leading to Aβ generation in AVs and its delayed degradation in lysosomes (E).
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fig8: Proposed models of AV accumulation leading to elevated Aβ levels. The schematic of macroautophagy depicts (A) the usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV buildup (B and C) are expected to promote Aβ generation and accumulation, including impaired or delayed maturation of autophagosomes to lysosomes (B) or acute maximum induction of macroautophagy (C). Within neurons, AVs normally progress to lysosomes efficiently and are rarely seen in neurons (D). In AD, the disrupted retrograde transport of AVs in dendrites represents one of several possible mechanisms that impede the maturation of AVs to lysosomes, leading to Aβ generation in AVs and its delayed degradation in lysosomes (E).

Mentions: We have also demonstrated, for the first time, that Aβ is generated during macroautophagy. Aβ production rises when macroautophagy is acutely stimulated, and AVs proliferate and fall when macroautophagy is inhibited. AVs are depleted by blocking either of the two independent signaling pathways for macroautophagy that converge on mTOR kinase activity: amino acid–mediated signaling and the PI3-kinase–dependent pathway. Conditions that either stimulate AV production and delay or impair maturation of AVs to lysosomes might be expected to increase the number of AVs and raise intracellular Aβ levels (Fig. 8). Aβ is believed to be generated at several sites within neurons, including endosomes, Golgi, and ER (Cataldo et al., 2004a), and this multiplicity of APP processing routes would account for our observations that considerable Aβ is still secreted from L/APP, SH-SY5Y, and N2a cells when macroautophagy is inhibited. Endocytic and autophagic pathways communicate extensively, and both Golgi and ER are turned over by macroautophagy (Dunn, 1990a), raising the possibility that each of these organelles could contribute to Aβ generation, in part, via macroautophagy. This communication between the macroautophagy and endosomal systems also provides one possible avenue for Aβ that is generated during macroautophagy to be released from cells, because late endosomes also communicate with endocytic recycling compartments (for review see Luzio et al., 2005). Extracellular release of some Aβ from AVs is also possible from exosomes, which is a mechanism proposed for prion release (Fevrier et al., 2005), or from the direct fusion of AVs with the plasma membrane (Jackson et al., 2005). It is worth noting, however, that the inefficient extracellular elimination of autophagy-generated Aβ may imply greater pathogenicity of this pool than the Aβ that is normally secreted because intracellular Aβ appears to be more cytotoxic than extracellular Aβ.


Macroautophagy--a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease.

Yu WH, Cuervo AM, Kumar A, Peterhoff CM, Schmidt SD, Lee JH, Mohan PS, Mercken M, Farmery MR, Tjernberg LO, Jiang Y, Duff K, Uchiyama Y, Näslund J, Mathews PM, Cataldo AM, Nixon RA - J. Cell Biol. (2005)

Proposed models of AV accumulation leading to elevated Aβ levels. The schematic of macroautophagy depicts (A) the usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV buildup (B and C) are expected to promote Aβ generation and accumulation, including impaired or delayed maturation of autophagosomes to lysosomes (B) or acute maximum induction of macroautophagy (C). Within neurons, AVs normally progress to lysosomes efficiently and are rarely seen in neurons (D). In AD, the disrupted retrograde transport of AVs in dendrites represents one of several possible mechanisms that impede the maturation of AVs to lysosomes, leading to Aβ generation in AVs and its delayed degradation in lysosomes (E).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2171227&req=5

fig8: Proposed models of AV accumulation leading to elevated Aβ levels. The schematic of macroautophagy depicts (A) the usual progression from autophagosomes (AP) to autophagolysosomes (APL) to lysosomes (L). Conditions that result in AV buildup (B and C) are expected to promote Aβ generation and accumulation, including impaired or delayed maturation of autophagosomes to lysosomes (B) or acute maximum induction of macroautophagy (C). Within neurons, AVs normally progress to lysosomes efficiently and are rarely seen in neurons (D). In AD, the disrupted retrograde transport of AVs in dendrites represents one of several possible mechanisms that impede the maturation of AVs to lysosomes, leading to Aβ generation in AVs and its delayed degradation in lysosomes (E).
Mentions: We have also demonstrated, for the first time, that Aβ is generated during macroautophagy. Aβ production rises when macroautophagy is acutely stimulated, and AVs proliferate and fall when macroautophagy is inhibited. AVs are depleted by blocking either of the two independent signaling pathways for macroautophagy that converge on mTOR kinase activity: amino acid–mediated signaling and the PI3-kinase–dependent pathway. Conditions that either stimulate AV production and delay or impair maturation of AVs to lysosomes might be expected to increase the number of AVs and raise intracellular Aβ levels (Fig. 8). Aβ is believed to be generated at several sites within neurons, including endosomes, Golgi, and ER (Cataldo et al., 2004a), and this multiplicity of APP processing routes would account for our observations that considerable Aβ is still secreted from L/APP, SH-SY5Y, and N2a cells when macroautophagy is inhibited. Endocytic and autophagic pathways communicate extensively, and both Golgi and ER are turned over by macroautophagy (Dunn, 1990a), raising the possibility that each of these organelles could contribute to Aβ generation, in part, via macroautophagy. This communication between the macroautophagy and endosomal systems also provides one possible avenue for Aβ that is generated during macroautophagy to be released from cells, because late endosomes also communicate with endocytic recycling compartments (for review see Luzio et al., 2005). Extracellular release of some Aβ from AVs is also possible from exosomes, which is a mechanism proposed for prion release (Fevrier et al., 2005), or from the direct fusion of AVs with the plasma membrane (Jackson et al., 2005). It is worth noting, however, that the inefficient extracellular elimination of autophagy-generated Aβ may imply greater pathogenicity of this pool than the Aβ that is normally secreted because intracellular Aβ appears to be more cytotoxic than extracellular Aβ.

Bottom Line: Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity.Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production.Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

View Article: PubMed Central - PubMed

Affiliation: Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.

ABSTRACT
Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before beta-amyloid (Abeta) deposits extracellularly in the presenilin (PS) 1/Abeta precursor protein (APP) mouse model of beta-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Abeta. Purified AVs contain APP and beta-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent gamma-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Abeta production. Our results, therefore, link beta-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

Show MeSH
Related in: MedlinePlus