Trafficking regulation of proteins in Alzheimer’s disease

Jiang, Shangtong; Li, Yanfang; Zhang, Xian; Bu, Guojun; Xu, Huaxi; Zhang, Yunwu

doi:10.1186/1750-1326-9-6

Cited by 124 publications

(122 citation statements)

References 196 publications

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“…These APP-CTFs are then retrogradely trafficked to the TGN for ␥-secretase cleavage and A␤ generation (19). APP retrograde trafficking is highly regulated because APP proteolysis is dynamic and can lead to rapid changes in A␤ production (58). A consequence of decreased APP-CTF trafficking to the TGN is the decrease in ␥-secretasemediated cleavage of APP-CTFs and the concomitant decrease in A␤ and AICD generation.…”

Section: Discussionmentioning

confidence: 99%

Cyclopamine Modulates γ-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation

Vorobyeva

Lee

Miller

et al. 2014

Journal of Biological Chemistry

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Background: Sterols can alter APP metabolism. Results: Cyclopamine, a phytosterol, alters APP-CTF degradation rate, decreases APP-CTF bioavailability for ␥-secretase cleavage, and reduces A␤ and AICD generation. Conclusion: Cyclopamine decreases A␤ and AICD production by altering APP-CTF retrograde trafficking. Significance: Cyclopamine is a novel modulator of APP metabolism and trafficking, which can illuminate new avenues for Alzheimer disease treatment.

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Section: Discussionmentioning

confidence: 99%

Cyclopamine Modulates γ-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation

Vorobyeva

Lee

Miller

et al. 2014

Journal of Biological Chemistry

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“…Alzheimer's disease is one of the most common neurodegenerative diseases and is primarily caused by the accumulation and deposition of neurotoxic β-amyloid (Aβ) peptides in vulnerable brain regions (Jiang et al, 2014;Lemere, 2013). Mitochondrial morphology has been found to be abnormal in degenerating dendrites in the brains of individuals with Alzheimer's disease (Saraiva et al, 1985).…”

Section: Introductionmentioning

confidence: 99%

Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology

Zhang

Shi

Zhang

et al. 2016

Journal of Cell Science

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Mitochondrial morphology is regulated by fusion and fission machinery. Impaired mitochondria dynamics cause various diseases, including Alzheimer's disease. Appoptosin (encoded by SLC25A38) is a mitochondrial carrier protein that is located in the mitochondrial inner membrane. Appoptosin overexpression causes overproduction of reactive oxygen species (ROS) and caspasedependent apoptosis, whereas appoptosin downregulation abolishes β-amyloid-induced mitochondrial fragmentation and neuronal death during Alzheimer's disease. Herein, we found that overexpression of appoptosin resulted in mitochondrial fragmentation in a manner independent of its carrier function, ROS production or caspase activation. Although appoptosin did not affect levels of mitochondrial outer-membrane fusion (MFN1 and MFN2), inner-membrane fusion (OPA1) and fission [DRP1 (also known as DNM1L) and FIS1] proteins, appoptosin interacted with MFN1 and MFN2, as well as with the mitochondrial ubiquitin ligase MITOL (also known as MARCH5) but not OPA1, FIS1 or DRP1. Appoptosin overexpression impaired the interaction between MFN1 and MFN2, and mitochondrial fusion. By contrast, co-expression of MFN1, MITOL and a dominant-negative form of DRP1, DRP1K38A , partially rescued appoptosin-induced mitochondrial fragmentation and apoptosis, whereas co-expression of FIS1 aggravated appoptosin-induced apoptosis. Together, our results demonstrate that appoptosin can interact with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology.

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“…The mechanisms underlying the retrieval of the IGF-II receptor overlap significantly with those of proteins involved in the intracellular trafficking of APP and BACE1. More importantly, GGA, PACS1, and retromer complex have been implicated in the control of APP processing (63,(67)(68)(69).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

Wang

Buggia-Prévot

Zavorka

et al. 2015

Molecular and Cellular Biology

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dAmyloid ␤ (A␤) peptides originating from amyloid precursor protein (APP) in the endosomal-lysosomal compartments play a critical role in the development of Alzheimer's disease (AD), the most common type of senile dementia affecting the elderly. Since insulin-like growth factor II (IGF-II) receptors facilitate the delivery of nascent lysosomal enzymes from the trans-Golgi network to endosomes, we evaluated their role in APP metabolism and cell viability using mouse fibroblast MS cells deficient in the murine IGF-II receptor and corresponding MS9II cells overexpressing the human IGF-II receptors. Our results show that IGF-II receptor overexpression increases the protein levels of APP. This is accompanied by an increase of ␤-site APP-cleaving enzyme 1 levels and an increase of ␤-and ␥-secretase enzyme activities, leading to enhanced A␤ production. At the cellular level, IGF-II receptor overexpression causes localization of APP in perinuclear tubular structures, an increase of lipid raft components, and increased lipid raft partitioning of APP. Finally, MS9II cells are more susceptible to staurosporine-induced cytotoxicity, which can be attenuated by ␤-secretase inhibitor. Together, these results highlight the potential contribution of IGF-II receptor to AD pathology not only by regulating expression/processing of APP but also by its role in cellular vulnerability. Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by severe memory loss followed by the deterioration of higher cognitive functions. Although most cases of AD occur sporadically after the age of 60 years, a small proportion of cases correspond to the early-onset (Ͻ60 years) autosomal dominant form of the disease. To date, mutations in three genes, the amyloid precursor protein (APP) gene on chromosome 21, the presenilin 1 (PSEN1) gene on chromosome 14, and the presenilin 2 (PSEN2) gene on chromosome 1, have been identified as the cause of a large proportion of early-onset familial AD (1-3). Additionally, inheritance of the ε4 allele of the apolipoprotein E (APOE) gene on chromosome 19 increases the risk of late-onset and sporadic AD. The neuropathological features associated with AD include the presence of extracellular ␤-amyloid (A␤) peptidecontaining neuritic plaques, intracellular tau-positive neurofibrillary tangles, and the loss of synapses and neurons in defined brain regions. Several lines of in vivo evidence suggest that A␤ peptides initiate or contribute to the neuronal loss and development of AD pathology (2, 4). A␤ peptides are generated from APP, a type I transmembrane protein, which can be processed either by nonamyloidogenic ␣-secretase or amyloidogenic ␤-secretase pathways (5, 6). The ␣-secretase cleaves APP within the A␤ domain, yielding soluble APP␣ and a 10-kDa C-terminal fragment (CTF-␣), which then can be processed by ␥-secretase to generate A␤ 17-40 /A␤ 17-42 fragments. The ␤-secretase, on the other hand, cleaves APP to generate soluble APP␤ and an A␤-containing Cterminal fragment (CTF-␤), which is fu...

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Trafficking regulation of proteins in Alzheimer’s disease

Cited by 124 publications

References 196 publications

Cyclopamine Modulates γ-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation

Cyclopamine Modulates γ-Secretase-mediated Cleavage of Amyloid Precursor Protein by Altering Its Subcellular Trafficking and Lysosomal Degradation

Appoptosin interacts with mitochondrial outer-membrane fusion proteins and regulates mitochondrial morphology

Overexpression of the Insulin-Like Growth Factor II Receptor Increases β-Amyloid Production and Affects Cell Viability

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