LRP1 Downregulates the Alzheimer’s β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking

Tanokashira, Daisuke; Motoki, Kazumi; Minegishi, Seiji; Hosaka, Ai; Mamada, Naomi; Tamaoka, Akira; Okada, Takashi; Lakshmana, Madepalli K.; Araki, Wataru

doi:10.1523/eneuro.0006-15.2015

Cited by 18 publications

(20 citation statements)

References 64 publications

(98 reference statements)

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“…To gain further insights into the mechanism underlying Aβ-O-induced elevation of BACE1, we analyzed the influence of Aβ-O on intraneuronal localization of BACE1 using immunocytochemistry. In control untreated neurons, endogenous BACE1 immunoreactivity was observed in neuronal soma and neurites, consistent with recent findings [ 23 , 24 ]. Interestingly, in neurons treated with Aβ-O for 3 days, the intensity of BACE1 immunoreactivity was higher relative to control, although levels in soma were comparable between control and Aβ-O-treated neurons (Fig.…”

Section: Resultssupporting

confidence: 92%

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Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

et al. 2015

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Backgroundβ-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is a membrane-bound aspartyl protease that initiates amyloid β-protein (Aβ) generation. Aberrant elevation of BACE1 levels in brains of Alzheimer’s disease (AD) patients may involve Aβ. In the present study, we used a neuron culture model system to investigate the effects of Aβ on BACE1 expression as well as the underlying mechanisms.ResultsRat primary cortical neurons were treated with relatively low concentrations (2.5 μM) of Aβ42 oligomers (Aβ-O) or fibrils (Aβ-F) for 2–3 days. Aβ-O induced a significant increase in protein levels of BACE1, while Aβ-F only had a marginal effect. Levels of amyloid precursor protein (APP) and the major α-secretase, ADAM10, remained unaltered upon treatment with both types of Aβ. Aβ-O treatment resulted in activation of eIF2α and caspase 3 in a time-dependent manner, with no changes in the endoplasmic reticulum (ER) stress marker, GRP78, indicating that a typical ER stress response is not induced under our experimental conditions. Furthermore, Aβ-O did not affect BACE1 mRNA expression but augmented the levels of exogenous BACE1 expressed via recombinant adenoviruses, indicating regulation of BACE1 protein expression, not at the transcriptional or translational but the post-translational level. Immunocytochemical analysis revealed that Aβ-O causes a significant increase in BACE1 immunoreactivity in neurites (both axons and dendrites), but not soma of neurons; this change appears relevant to the mechanism of Aβ-O-induced BACE1 elevation, which may involve impairment of BACE1 trafficking and degradation. In contrast, Aβ-O had no effect on APP immunoreactivity.ConclusionOur results collectively suggest that Aβ oligomers induce BACE1 elevation via a post-translational mechanism involving its altered subcellular distribution in neurons, which possibly triggers a vicious cycle of Aβ generation, thus contributing to the pathogenetic mechanism of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-015-0163-5) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 92%

“…5 ). A few molecules are involved in BACE1 degradation, among which GGA3 has been most extensively investigated [ 14 , 24 , 32 , 33 ]. GGA3 appears to participate in BACE1 sorting from endosomes to lysosomes, and caspase-mediated depletion of GGA3 stabilizes BACE1 [ 14 , 35 ].…”

Section: Discussionmentioning

confidence: 99%

Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

et al. 2015

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“…BACE1 structure, subcellular localization and/or activity are modulated by interaction with a large number of proteins including BRI3, GGA's, LRP1, and nicastrin among others. [41][42][43] We have shown that FIGURE 6 ORP150 regulates BACE1 expression under ER and oxidative stress. A, HEK293-BACE1 stable cells were treated with 4 and 10 μg/mL of tunicamycin for ER stress.…”

Section: Discussionmentioning

confidence: 97%

ORP150‐CHIP chaperone antagonism control BACE1‐mediated amyloid processing

Chanana

Pati

2018

J of Cellular Biochemistry

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BACE1, a key protein involved in Alzheimer's progression, initiates Aβ42 generation that induce senile plaques in brain. However, the role of chaperone synergy or antagonism on BACE1-mediated amyloid processing is unknown. We have discovered that BACE1 as well as Aβ42 are antagonistically controlled by ER chaperone ORP150 and cellular chaperone CHIP. We have shown ORP150 as a chaperone interacts with and stabilizes BACE1 at post-translational level. Furthermore, ORP150 enhances BACE1-mediated amyloid processing thus masking CHIP-mediated BACE1 degradation. Conversely, siORP150 reversed the chaperone function of ORP150 resulting in BACE1 degradation. ORP150 and CHIP demonstrate antagonism under normal and stress conditions wherein they inversely regulate each other thus affecting BACE1 level. In conclusion, we have uncovered for the first time a phenomenon of chaperone antagonism on BACE1-mediated Aβ42 generation. Future strategy would require both suppression of ORP150 as well as activation of E3-ligase activity of CHIP that might prevent Aβ42 in Alzheimer's disease.

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“…Jaeger et al (72) also revealed that dysfunction of LRP1 at the blood brain barrier may be associated with increased Aβ accumulation and progression of AD. Recently, LRP1 was associated with downregulation of β-site APP-cleaving enzyme 1 (BACE1) and, thus, affects generation of Aβ by cleavage of the APP (73).…”

Section: Angiotensin-converting Enzyme (Ace)mentioning

confidence: 99%

Unraveling the genes implicated in Alzheimer's disease

Giri¹,

Shah²,

Upreti³

et al. 2017

Biomedical Reports

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Abstract. Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and it is the most common form of dementia in the elderly. Early onset AD is caused by mutations in three genes: Amyloid-β precursor protein, presenilin 1 (PSEN1) and PSEN2. Late onset AD (LOAD) is complex and apolipoprotein E is the only unanimously accepted genetic risk factor for its development. Various genes implicated in AD have been identified using advanced genetic technologies, however, there are many additional genes that remain unidentified. The present review highlights the genetics of early and LOAD and summarizes the genes involved in different signaling pathways. This may provide insight into neurodegenerative disease research and will facilitate the development of effective strategies to combat AD.

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LRP1 Downregulates the Alzheimer’s β-Secretase BACE1 by Modulating Its Intraneuronal Trafficking

Abstract: The β-secretase called BACE1 is a membrane-associated protease that initiates the generation of amyloid β-protein, a key event in Alzheimer’s disease. However, the mechanism of inraneuronal regulation of BACE1 is poorly understood.

Cited by 18 publications

References 64 publications

Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

Amyloid β-protein oligomers upregulate the β-secretase, BACE1, through a post-translational mechanism involving its altered subcellular distribution in neurons

ORP150‐CHIP chaperone antagonism control BACE1‐mediated amyloid processing

Unraveling the genes implicated in Alzheimer's disease

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