Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway

Das, Utpal; Scott, David; Ganguly, Archan; Koo, Edward H.; Tang, Yong; Roy, Subhojit

doi:10.1016/j.neuron.2013.05.035

Cited by 215 publications

(249 citation statements)

References 42 publications

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“…SORL1 acts as a retention factor for APP in the TGN and thus regulates APP trafficking (5). Some reports have implicated the endosomes in this process, but endosomal function could be affected by altered Golgi-mediated trafficking under disease conditions (6,7). Furthermore, several recent reports have suggested that the amyloidogenic processing of APP, which produces Aβ, may occur in the Golgi and the late secretory pathway (2,4).…”

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confidence: 99%

Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Joshi

Chi

Huang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

155

182

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Golgi fragmentation occurs in neurons of patients with Alzheimer's disease (AD), but the underlying molecular mechanism causing the defects and the subsequent effects on disease development remain unknown. In this study, we examined the Golgi structure in APPswe/PS1ΔE9 transgenic mouse and tissue culture models. Our results show that accumulation of amyloid beta peptides (Aβ) leads to Golgi fragmentation. Further biochemistry and cell biology studies revealed that Golgi fragmentation in AD is caused by phosphorylation of Golgi structural proteins, such as GRASP65, which is induced by Aβ-triggered cyclin-dependent kinase-5 activation. Significantly, both inhibition of cyclin-dependent kinase-5 and expression of nonphosphorylatable GRASP65 mutants rescued the Golgi structure and reduced Aβ secretion by elevating α-cleavage of the amyloid precursor protein. Our study demonstrates a molecular mechanism for Golgi fragmentation and its effects on amyloid precursor protein trafficking and processing in AD, suggesting Golgi as a potential drug target for AD treatment.Golgi stacking | APP processing | GRASP55 | amyloidogenic

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mentioning

confidence: 99%

Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Joshi

Chi

Huang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

155

182

View full text Add to dashboard Cite

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“…We hypothesized that the decrease in BACE1 protein levels was a result of increased trafficking of BACE1 to the lysosomes and reduction of BACE1 in recycling endosomes, the intracellular site where BACE1 meets and processes APP (55)(56)(57). We found that USP8 depletion increased BACE1 localization in the early endosomes and the lysosomes, while decreasing BACE1 contained in the recycling endosomes.…”

Section: Discussionmentioning

confidence: 99%

The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

Yeates¹,

Tesco

2016

Journal of Biological Chemistry

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The ␤-site amyloid precursor protein-cleaving enzyme (BACE1) is the rate-limiting enzyme in the production of amyloid-␤, the toxic peptide that accumulates in the brain of subjects affected by Alzheimer disease. Our previous studies have shown that BACE1 is degraded via the lysosomal pathway and that that depletion of the trafficking molecule Golgi-localized ␥-ear-containing ARF-binding protein 3 (GGA3) results in increased BACE1 levels and activity because of impaired lysosomal degradation. We also determined that GGA3 regulation of BACE1 levels requires its ability to bind ubiquitin. Accordingly, we reported that BACE1 is ubiquitinated at lysine 501 and that lack of ubiquitination at lysine 501 produces BACE1 stabilization. Ubiquitin conjugation is a reversible process mediated by deubiquitinating enzymes. The ubiquitin-specific peptidase 8 (USP8), an endosome-associated deubiquitinating enzyme, regulates the ubiquitination, trafficking, and lysosomal degradation of several plasma membrane proteins. Here, we report that RNAi-mediated depletion of USP8 reduced levels of both ectopically expressed and endogenous BACE1 in H4 human neuroglioma cells. Moreover, USP8 depletion increased BACE1 ubiquitination, promoted BACE1 accumulation in the early endosomes and late endosomes/lysosomes, and decreased levels of BACE1 in the recycling endosomes. We also found that decreased BACE1 protein levels were accompanied by a decrease in BACE1-mediated amyloid precursor protein cleavage and amyloid-␤ levels. Our findings demonstrate that USP8 plays a key role in the trafficking and degradation of BACE1 by deubiquitinating lysine 501. These studies suggest that therapies able to accelerate BACE1 degradation (e.g. by increasing BACE1 ubiquitination) may represent a potential treatment for Alzheimer disease.

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“…Immunohistochemistry staining also showed Aβ42 were existed in AEL (autophagy-endosomal-lysosomal) vesicles in Drosophila neurons [62]. Another study applied on neuron showed that although APP and its processing enzyme BACE1 should be separated into distinct vesicles under normal condition, they showed strong co-localization and co-trafficking into autophagy-lssosome pathways under glycine/ NMDA-receptor agonist /K+ or GABA A antagonist Picrotoxin (PTX) stimulations [63]. This result indicated under some certain pathological conditions, the convergence of APP and BACE1 in autophagosomes may perform as novel place for Aβ generation.…”

Section: Autophagy Dysfunction and Ad-related Pathologymentioning

confidence: 98%

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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Activity-Induced Convergence of APP and BACE-1 in Acidic Microdomains via an Endocytosis-Dependent Pathway

Cited by 215 publications

References 42 publications

Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

Aβ-induced Golgi fragmentation in Alzheimer’s disease enhances Aβ production

The Endosome-associated Deubiquitinating Enzyme USP8 Regulates BACE1 Enzyme Ubiquitination and Degradation

The role of autophagy in Alzheimer's disease

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