Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons

Yang, Guizhi; Yang, Miao; Lim, Yoon Pin; Lu, Jianjun; Wang, Ting‐Hua; Qi, Jian-Guo; Zhong, Jin‐Hua; Zhou, Xin‐Fu

doi:10.1111/j.1471-4159.2012.07845.x

Cited by 30 publications

(20 citation statements)

References 62 publications

(135 reference statements)

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“…The biotinylation assay for APP and BACE1 was performed as previously described (Yang et al . ). Briefly, cortical neurons from P0 p75 −/− and p75 +/+ mice were isolated and cultured in six‐well plates.…”

Section: Methodsmentioning

confidence: 97%

p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis

Saadipour

Mañucat-Tan

Lim

et al. 2017

Journal of Neurochemistry

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deposition of amyloid beta (Aβ) and dysregulation of neurotrophic signaling, causing synaptic dysfunction, loss of memory, and cell death. The expression of p75 neurotrophin receptor is elevated in the brain of AD patients, suggesting its involvement in this disease. However, the exact mechanism of its action is not yet clear. Here, we show that p75 interacts with beta-site amyloid precursor protein cleaving enzyme-1 (BACE1), and this interaction is enhanced in the presence of Aβ. Our results suggest that the colocalization of BACE1 and amyloid precursor protein (APP) is increased in the presence of both Aβ and p75 in cortical neurons. In addition, the localization of APP and BACE1 in early endosomes is increased in the presence of Aβ and p75. An increased phosphorylation of APP-Thr668 and BACE1-Ser498 by c-Jun N-terminal kinase (JNK) in the presence of Aβ and p75 could be responsible for this localization. In conclusion, our study proposes a potential involvement in amyloidogenesis for p75, which may represent a future therapeutic target for AD. Cover Image for this Issue: doi. 10.1111/jnc.14163.

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Section: Methodsmentioning

confidence: 97%

p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis

Saadipour

Mañucat-Tan

Lim

et al. 2017

Journal of Neurochemistry

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“…Lactadherin amyloid, a deposit known as medin that is localized in aortic medium, occurs in virtually all individuals older than 60 years. The huntingtinassociated protein 1 modulates the A␤PP subcellular trafficking pathway, thus negatively regulating A␤ production in neurons (78). Loss of superoxide dismutase (SOD) increases production of A␤ in neurons and SHSY5Y cells, an effect caused by enhanced A␤PP processing by the ␤-site A␤PP-cleaving enzyme (79), whereas earlier studies have shown that overexpression of superoxide dismutase reduces A␤ neurotoxicity (80).…”

Section: Other Amyloid Proteinsmentioning

confidence: 99%

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

Luo

Wärmländer

Gräslund

et al. 2016

Journal of Biological Chemistry

126

108

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Many protein folding diseases are intimately associated with accumulation of amyloid aggregates. The amyloid materials formed by different proteins/peptides share many structural similarities, despite sometimes large amino acid sequence differences. Some amyloid diseases constitute risk factors for others, and the progression of one amyloid disease may affect the progression of another. These connections are arguably related to amyloid aggregates of one protein being able to directly nucleate amyloid formation of another, different protein: the amyloid cross-interaction. Here, we discuss such cross-interactions between the Alzheimer disease amyloid-␤ (A␤) peptide and other amyloid proteins in the context of what is known from in vitro and in vivo experiments, and of what might be learned from clinical studies. The aim is to clarify potential molecular associations between different amyloid diseases. We argue that the amyloid cascade hypothesis in Alzheimer disease should be expanded to include cross-interactions between A␤ and other amyloid proteins.Alzheimer disease (AD) 3 is the most common form of elderly dementia. Its causes have not yet been clearly elucidated. The two classical AD lesions are depositions of intracellular neurofibrillary tau tangles and extracellular deposits of aggregated amyloid-␤ (A␤) peptides in amyloid plaques in the gray matter of the brain, mainly the hippocampus and neocortex. A␤ is a 36 -43-residue peptide cleaved from the amyloid-␤ protein precursor (A␤PP) by ␥-secretase and ␤-secretase enzymes.Some A␤PP and A␤ mutations increase A␤ production and deposition and/or extend the half-life of A␤ in the brain, but only a fraction (5%) of Alzheimer disease is familial AD (1). Several studies indicate that alterations of the pathologies of other amyloid proteins such as ␣-synuclein (2) and tau (3) are observed in familial AD.The amyloid cascade hypothesis suggests that deposition of A␤ aggregates in brain plays a vital role in AD development (4). The amyloid form of A␤ aggregates is generally defined by in vitro observations: originally by the so-called cross-␤ x-ray diffraction pattern or by observation of fibril structures in microscopy (transmission electron microscopy or atomic force microscopy) (5). Molecular probes recognizing the formation of certain ordered molecular structures include Congo red and thioflavin T, which change their optical properties when bound to amyloid material (5). The terms "on-pathway" and "off-pathway" intermediates are used to differentiate between self-aggregated A␤ species that lead to amyloid formation and those that do not. Missense mutations in the A␤PP, apoE, PS1, and PS2 genes can increase accumulation and toxicity of A␤ aggregates, and the "on-pathway" intermediate aggregates seem to be the most cell-damaging species (6). This provides strong support for the amyloid cascade hypothesis, which nevertheless remains disputed.Although two recent reviews (7, 8) respectively reject and support the amyloid cascade hypothesis, they both agree on one poin...

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“…Since APP is cleaved by various secretases during its trafficking within the cell, identifying proteins that can regulate APP transport and thus affect its processing for Aβ generation may shed light on elucidating the pathogenesis of AD. Recent studies have identified multiple APP-interacting proteins, such as Mints[13], LRP[14,15], RanBP9[16], SorLA/LR11[17,18], AP-4[19], FBL2[20], APLP1[21], SNX17[22], ApoER2[23], HAP1[24] and flotillin-2[25], that can regulate APP trafficking and Aβ generation.…”

Section: Introductionmentioning

confidence: 99%

SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

Feng

Niu

et al. 2015

Mol Neurobiol

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Amyloid-β (A(β) peptide plays an essential role in the pathogenesis of Alzheimer's disease (AD) and is generated from amyloid-β precursor protein (APP) through sequential proteolytic cleavages by β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. Trafficking dysregulation of APP, BACE1 and γ-secretase may affect Aβ generation and disease pathogenesis. Sorting nexin 15 (SNX15) is known to regulate protein trafficking. Here we report that SNX15 is abundantly expressed in mouse neurons and astrocytes. In addition, we show that although not affecting the protein levels of APP, BACE1 and γ-secretase components and the activity of BACE1 and γ-secretase, overexpression and downregulation of SNX15 reduces and promotes Aβ production, respectively. Furthermore, we find that overexpression of SNX15 increases APP protein levels in cell surface through accelerating APP recycling, whereas downregulation of SNX15 has an opposite effect. Finally, we show that exogenous expression of human SNX15 in the hippocampal dentate gyrus by adeno-associated virus (AAV) infection can significantly reduce Aβ pathology in the hippocampus and improve short-term working memory in the APPswe/PSEN1dE9 double transgenic AD model mice. Together, our results suggest that SNX15 regulates the recycling of APP to cell surface and thus its processing for Aβ generation.

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Huntingtin associated protein 1 regulates trafficking of the amyloid precursor protein and modulates amyloid beta levels in neurons

Cited by 30 publications

References 62 publications

p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis

p75 neurotrophin receptor interacts with and promotes BACE1 localization in endosomes aggravating amyloidogenesis

Cross-interactions between the Alzheimer Disease Amyloid-β Peptide and Other Amyloid Proteins: A Further Aspect of the Amyloid Cascade Hypothesis

SNX15 Regulates Cell Surface Recycling of APP and Aβ Generation

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