Yu, W.H. et al. Macroautophagy-a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J. Cell Biol. 171, 87-98

Center for Dementia Research, Nathan Kline Institute, Orangeburg, NY 10962, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 11/2005; 171(1):87-98. DOI: 10.1083/jcb.200505082
Source: PubMed


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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    • "The stimulation of autophagy by rapamycin (a classical mTOR inhibitor) or starvation results in the translocation of the g-secretase complex from a predominantly endosomal/ER pool to AVs, where this complex accumulates transiently and becomes the largest cellular pool of g-secretase activity (Yu et al., 2005). Under these conditions, Ab production rises two-fold over that in autophagy-suppressed cells and Ab immunoreactivity appears within AVs (Yu et al., 2005). Taking advantage of an Atg5 knockdown human embryonic kidney (HEK293) cell line, Ohta et al. (2010) presented an exciting mechanism connecting autophagy and Ab generation. "
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    ABSTRACT: Autophagy is a housekeeping process responsible for the bulk degradation of misfolded protein aggregates and damaged organelles through the lysosomal machinery. Given its key role as a cellular quality control mechanism, autophagy is now a focus of intense scrutiny in Alzheimer's disease (AD). The hallmarks of this devastating neurodegenerative disease are the accumulation of misfolded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein and neuronal loss, which are accompanied by mitochondrial dysfunction and endoplasmic reticulum (ER) stress, suggesting that faulty autophagy is a contributing factor to AD pathology. Indeed, the AD brain is characterized by a massive accumulation of autophagic vacuoles within large swellings along dystrophic neurites and defects at different steps of the autophagic-lysosomal pathway. In this sense, this review provides an overview on the role of autophagy on Aβ metabolism, tau processing and clearance, and the contribution of ER-phagy and mitophagy to AD pathology. From a therapeutic perspective, this review also intends to clarify whether, when, and how autophagy can be targeted to efficaciously counteract AD-related symptomatic and neuropathological features.
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    • "More recently, in vivo preclinical assays using transcranial electromagnetic treatment (TMS) schemes, suggested that, besides AD, TMS's mechanisms of action provide an effective therapeutic potential against other neurologic disorders/injuries, such as Parkinson's disease, traumatic brain injury, and stroke (Arendash et al., 2012; Arendash, 2012). Of interest, at molecular level, it was reported that in AD patients, the autophagic process, and in particular the maturation of autophagosomes, is impaired (Yu et al., 2005). "
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    • "In AD model mouse and AD brains there is evidence that the autophagy is compromised as accumulations of autophagosomes and late autophagic vesicles (AVs) have been observed in dystrophic and degenerating neuritis [11] [12] [13]. Moreover, AVs were suggested as intracellular Ab-generating compartments [13] [14], thus contributing to the worsening of AD pathology. There is also compelling evidence that tau is cleared by autophagy [15] [16] [17]. "
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    ABSTRACT: We previously showed that NDP52 (also known as calcoco2) plays a role as an autophagic receptor for phosphorylated tau facilitating its clearance via autophagy. Here, we examined the expression and association of NDP52 with autophagy-regulated gene (ATG) proteins including LC3, as well as phosphorylated tau and amyloid-beta (Aβ) in brains of an AD mouse model. NDP52 was expressed not only in neurons, but also in microglia and astrocytes. NDP52 co-localized with ATGs and phosphorylated tau as expected since it functions as an autophagy receptor for phosphorylated tau in brain. Compared to wild-type mice, the number of autophagic vesicles (AVs) containing NDP52 in both cortex and hippocampal regions was significantly greater in AD model mice. Moreover, the protein levels of NDP52 and phosphorylated tau together with LC3-II were also significantly increased in AD model mice, reflecting autophagy impairment in the AD mouse model. By contrast, a significant change in p62/SQSTM1 level was not observed in this AD mouse model. NDP52 was also associated with intracellular Aβ, but not with the extracellular Aβ of amyloid plaques. We conclude that NDP52 is a key autophagy receptor for phosphorylated tau in brain. Further our data provide clear evidence for autophagy impairment in brains of AD mouse model, and thus strategies that result in enhancement of autophagic flux in AD are likely to be beneficial.
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