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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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Immunolocalization of PS1 in plaques and AVs within dystrophic neurites in AD and PS1/APP mice. Cingulate cortex from 9-mo-old PS1/APP mice immunolabeled with PS1 antibody and NT1 showed that PS1 localized to plaques (A). At higher magnification, anti-PS1 antibodies strongly labeled neuritic profiles that were distributed within the plaque corona (B). PS1 immunoreactivity is identified by IEM in AVs within dystrophic neurites of PS1/APP animals (C and D) and human brain (E and F) by IEM. Arrowheads identify tubulovesicular membrane labeling. PS1 (C–F, arrows) was localized on the outer limiting membrane of the AV but not in mitochondria (Mito) or on plasma membranes (PM). IEM followed by silver stain enhancement for PS1 was performed on a human brain that was diagnosed for AD (F).
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fig3: Immunolocalization of PS1 in plaques and AVs within dystrophic neurites in AD and PS1/APP mice. Cingulate cortex from 9-mo-old PS1/APP mice immunolabeled with PS1 antibody and NT1 showed that PS1 localized to plaques (A). At higher magnification, anti-PS1 antibodies strongly labeled neuritic profiles that were distributed within the plaque corona (B). PS1 immunoreactivity is identified by IEM in AVs within dystrophic neurites of PS1/APP animals (C and D) and human brain (E and F) by IEM. Arrowheads identify tubulovesicular membrane labeling. PS1 (C–F, arrows) was localized on the outer limiting membrane of the AV but not in mitochondria (Mito) or on plasma membranes (PM). IEM followed by silver stain enhancement for PS1 was performed on a human brain that was diagnosed for AD (F).

Mentions: Multiple tubulovesicular compartments that were implicated in APP metabolism, such as the ER–Golgi and endosomes, become components of AVs either as substrates or by contributing to the limiting membrane of autophagosomes (Dunn, 1990a). Moreover, APP, β-site APP cleaving enzyme, and PS1 are reported to be abundant within neuritic plaques (Leuba et al., 2005), raising the possibility that these components are localized in AVs. We confirmed that neuritic plaques of PS1/APP mice are intensely labeled with a monoclonal antibody to PS1 (Fig. 3, A and B). Based on IEM, AVs were the principle immunoreactive structures within the dystrophic neurite, accounting for >90% of PS1 immunolabeling (Fig. 3, C–F). In the brains of both PS1/APP mice (Fig. 3, C and D) and AD patients (Fig. 3, E and F), PS1 antibody predominantly decorated the double-limiting membranes of AVs or single or double membranes within AVs (Fig. 3, arrows). Tubulovesicular membranes in the adjacent normal neurites were the only other immunolabeled structures that were detected in the neuropil (Fig. 3 D, arrowheads), which is consistent with the expected contribution of PS1-rich smooth ER to AV formation (Culvenor et al., 1997). Mitochondria, plasma membranes, small vesicles, and cytoplasm were essentially devoid of gold, underscoring the specificity of immunolocalization.


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)

Immunolocalization of PS1 in plaques and AVs within dystrophic neurites in AD and PS1/APP mice. Cingulate cortex from 9-mo-old PS1/APP mice immunolabeled with PS1 antibody and NT1 showed that PS1 localized to plaques (A). At higher magnification, anti-PS1 antibodies strongly labeled neuritic profiles that were distributed within the plaque corona (B). PS1 immunoreactivity is identified by IEM in AVs within dystrophic neurites of PS1/APP animals (C and D) and human brain (E and F) by IEM. Arrowheads identify tubulovesicular membrane labeling. PS1 (C–F, arrows) was localized on the outer limiting membrane of the AV but not in mitochondria (Mito) or on plasma membranes (PM). IEM followed by silver stain enhancement for PS1 was performed on a human brain that was diagnosed for AD (F).
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2171227&req=5

fig3: Immunolocalization of PS1 in plaques and AVs within dystrophic neurites in AD and PS1/APP mice. Cingulate cortex from 9-mo-old PS1/APP mice immunolabeled with PS1 antibody and NT1 showed that PS1 localized to plaques (A). At higher magnification, anti-PS1 antibodies strongly labeled neuritic profiles that were distributed within the plaque corona (B). PS1 immunoreactivity is identified by IEM in AVs within dystrophic neurites of PS1/APP animals (C and D) and human brain (E and F) by IEM. Arrowheads identify tubulovesicular membrane labeling. PS1 (C–F, arrows) was localized on the outer limiting membrane of the AV but not in mitochondria (Mito) or on plasma membranes (PM). IEM followed by silver stain enhancement for PS1 was performed on a human brain that was diagnosed for AD (F).
Mentions: Multiple tubulovesicular compartments that were implicated in APP metabolism, such as the ER–Golgi and endosomes, become components of AVs either as substrates or by contributing to the limiting membrane of autophagosomes (Dunn, 1990a). Moreover, APP, β-site APP cleaving enzyme, and PS1 are reported to be abundant within neuritic plaques (Leuba et al., 2005), raising the possibility that these components are localized in AVs. We confirmed that neuritic plaques of PS1/APP mice are intensely labeled with a monoclonal antibody to PS1 (Fig. 3, A and B). Based on IEM, AVs were the principle immunoreactive structures within the dystrophic neurite, accounting for >90% of PS1 immunolabeling (Fig. 3, C–F). In the brains of both PS1/APP mice (Fig. 3, C and D) and AD patients (Fig. 3, E and F), PS1 antibody predominantly decorated the double-limiting membranes of AVs or single or double membranes within AVs (Fig. 3, arrows). Tubulovesicular membranes in the adjacent normal neurites were the only other immunolabeled structures that were detected in the neuropil (Fig. 3 D, arrowheads), which is consistent with the expected contribution of PS1-rich smooth ER to AV formation (Culvenor et al., 1997). Mitochondria, plasma membranes, small vesicles, and cytoplasm were essentially devoid of gold, underscoring the specificity of immunolocalization.

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