Autophagy-Related Protein 7 Deficiency in Amyloid β (Aβ) Precursor Protein Transgenic Mice Decreases Aβ in the Multivesicular Bodies and Induces Aβ Accumulation in the Golgi

Nilsson, Per; Sekiguchi, Masaki; Akagi, Tomonori; Izumi, Shinichi; Komori, Toshihisa; Hui, Kelvin; Sörgjerd, Karin; Tanaka, Motomasa; Saito, Takashi; Iwata, Nobuhisa; Saido, Takaomi C.

doi:10.1016/j.ajpath.2014.10.011

Cited by 82 publications

(52 citation statements)

References 42 publications

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“…These findings may be reconciled considering that the APP-PSEN1 mice exhibit a very strong amyloidogenic processing of APP (PSEN1-driven APP processing), while our model exhibits mild amyloidogenic processing (APP-only), suggesting a reduced availability of extracellular Aβ peptides for plaque formation. In this regard, our results are consistent with those reported in the “APP-only” transgenic mice with ATG7-deficiency 51 . In this case, impaired autophagy influences unconventional secretion of Aβ to the extracellular space and thereby affects Aβ plaque formation.…”

Section: Discussionsupporting

confidence: 92%

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

et al. 2016

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Autophagy is a highly coordinated process that is controlled at several levels including transcriptional regulation. Here, we identify the transcription factor NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) as a regulator of autophagy gene expression and its relevance in a mouse model of Alzheimer disease (AD) that reproduces impaired APP (amyloid β precursor protein) and human (Hs)MAPT/TAU processing, clearance and aggregation. We screened the chromatin immunoprecipitation database ENCODE for 2 proteins, MAFK and BACH1, that bind the NFE2L2-regulated enhancer antioxidant response element (ARE). Using a script generated from the JASPAR's consensus ARE sequence, we identified 27 putative AREs in 16 autophagy-related genes. Twelve of these sequences were validated as NFE2L2 regulated AREs in 9 autophagy genes by additional ChIP assays and quantitative RT-PCR on human and mouse cells after NFE2L2 activation with sulforaphane. Mouse embryo fibroblasts of nfe2l2-knockout mice exhibited reduced expression of autophagy genes, which was rescued by an NFE2L2 expressing lentivirus, and impaired autophagy flux when exposed to hydrogen peroxide. NFE2L2-deficient mice co-expressing HsAPPV717I and HsMAPTP301L, exhibited more intracellular aggregates of these proteins and reduced neuronal levels of SQSTM1/p62, CALCOCO2/NDP52, ULK1, ATG5 and GABARAPL1. Also, colocalization of HsAPPV717I and HsMAPTP301L with the NFE2L2-regulated autophagy marker SQSTM1/p62 was reduced in the absence of NFE2L2. In AD patients, neurons expressing high levels of APP or MAPT also expressed SQSTM1/p62 and nuclear NFE2L2, suggesting their attempt to degrade intraneuronal aggregates through autophagy. This study shows that NFE2L2 modulates autophagy gene expression and suggests a new strategy to combat proteinopathies.

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Section: Discussionsupporting

confidence: 92%

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

et al. 2016

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“…Measurement of extracellular Aβ in autophagy-deficient mice revealed that the Aβ secretion was reduced by 90%, while restoration of autophagy enhanced Aβ secretion to normal levels [64]. There is another recent work has also found in ATG7 knockdown mice, the secretion Aβ was largely reduced, which was accompanied by a significant intracellular Aβ accumulation [65].…”

Section: Autophagy Dysfunction and Ad-related Pathologymentioning

confidence: 91%

The role of autophagy in Alzheimer's disease

Li¹,

Sun²

2017

J Syst Integr Neurosci

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Autophagy is a key pathway to clear cellular abnormal protein aggregates, and is essential for protein homeostasis and neuronal health. Several studies have shown autophagy deficits may occur in early stage of Alzheimer's disease (AD). Regarding to Alzheimer's disease, autophagy itself plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its dysfunction may lead to the progress or aggravate of AD. By considering all published evidences, autophagy may be considered as a new target for developing AD targeted drugs. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD, and the potential therapeutic effects of autophagy modulators in AD.

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“…Considering that Aβ secretion from the intra to extra cellular space of a neuron is positively correlated with the autophagy induction level [29][30][31], we assume the Aβ secretion specific rate R sec to be proportional to the degree of amino acid-and ATP-dependent…”

Section: Secretion and Clearance Of Amyloid-βmentioning

confidence: 99%

“…Aβ is degraded preferentially via autophagy; yet during late stages of AD autophagosomes fail to fuse with lysosomes [28]. In addition, the Aβ secretion rate depends on the autophagy activity [29][30][31]: the secretion rate is reduced in mice lacking autophagy-related gene 7 (Atg7) [30]. On the other hand, the autophagic activity is influenced by the intracellular Aβ concentration [28,[32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Computational modeling of the effects of autophagy on amyloid-β peptide levels

Han

Kim

Choi

2020

Theor Biol Med Model

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Background: Autophagy is an evolutionarily conserved intracellular process that is used for delivering proteins and organelles to the lysosome for degradation. For decades, autophagy has been speculated to regulate amyloid-β peptide (Aβ) accumulation, which is involved in Alzheimer's disease (AD); however, specific autophagic effects on the Aβ kinetics only have begun to be explored. Results:We develop a mathematical model for autophagy with respect to Aβ kinetics and perform simulations to understand the quantitative relationship between Aβ levels and autophagy activity. In the case of an abnormal increase in the Aβ generation, the degradation, secretion, and clearance rates of Aβ are significantly changed, leading to increased levels of Aβ. When the autophagic Aβ degradation is defective in addition to the increased Aβ generation, the Aβregulation failure is accompanied by elevated concentrations of autophagosome and autolysosome, which may further clog neurons. Conclusions: The model predicts that modulations of different steps of the autophagy pathway (i.e., Aβ sequestration, autophagosome maturation, and intralysosomal hydrolysis) have significant step-specific and combined effects on the Aβ levels and thus suggests therapeutic and preventive implications of autophagy in AD.

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Autophagy-Related Protein 7 Deficiency in Amyloid β (Aβ) Precursor Protein Transgenic Mice Decreases Aβ in the Multivesicular Bodies and Induces Aβ Accumulation in the Golgi

Cited by 82 publications

References 42 publications

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

Transcription factor NFE2L2/NRF2 is a regulator of macroautophagy genes

The role of autophagy in Alzheimer's disease

Computational modeling of the effects of autophagy on amyloid-β peptide levels

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