BACE1 mRNA Expression in Alzheimer's Disease Postmortem Brain Tissue

Coulson, David T.R.; Beyer, Nancy; Quinn, Joe G.; Brockbank, Simon; Hellemans, Jan; Irvine, G. Brent; Ravid, Rivka; Johnston, Janet

doi:10.3233/jad-2010-101254

Cited by 63 publications

(36 citation statements)

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“…In addition, we observed a significant increase in BACE1 expression in AD subjects as compared with healthy controls (Fig. 7a and c), which is consistent with previous studies showing elevated levels of BACE1 mRNA (Coulson et al, 2010) and protein (Fukumoto et al, 2002; Harada et al, 2006; Holsinger et al, 2002; Li et al, 2004; Tyler et al, 2002; Yang et al, 2003) in the AD brain. Total PACS1 levels were not significantly changed (Fig.…”

Section: Resultssupporting

confidence: 92%

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate limiting step in the generation of β-amyloid (Aβ) during Alzheimer’s disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in the endocytic compartments, where the acidic pH is optimal for its activity. However mechanisms that regulate the endosome-to-TGN retrieval of BACE1 under physiological conditions remain unclear. Here we show the Par polarity complex containing Par3 and aPKC facilitates BACE1 retrograde trafficking from the endosomes to the TGN. We further show that Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498. Finally, we found that Ser498 phosphorylation promotes the interaction between BACE1 and PACS1, which is necessary for the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in the AD pathogenic process. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1, and shed light on the mechanisms of AD pathogenesis.

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Section: Resultssupporting

confidence: 92%

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Sun

Zhang

2017

Neurobiology of Aging

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“…RNA is assumed to degrade from a 5 0 to 3 0 direction but in vivo this might be a more haphazard process with involvement of 3 0 -5 0 exonucleases and endonucleases. Even in the absence of 3 0 directed degradation, oligo dT-primed cDNA could still bias particular assays targeting longer transcripts with 5 0 amplicon locations [52]. However, we saw no relationship between either the transcript length, or amplicon position, and the strength of correlations with RIN across the nine transcripts assayed.…”

Section: Strengths and Weaknessesmentioning

confidence: 79%

The alternative splicing of the apolipoprotein E gene is unperturbed in the brains of Alzheimer’s disease patients

et al. 2014

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The prevalence of Alzheimer's disease (AD) is increasing rapidly worldwide due to an ageing population and a lack of disease modifying therapeutics. In monogenic forms of AD mutations lead to the accumulation of neurotoxic peptides called beta-amyloid. Beta-amyloid accumulation is also postulated to precipitate sporadic AD although the pathogenesis of this common form remains largely unknown. The two leading risk factors for sporadic AD are ageing and the possession of the APOE epsilon 4 allele. Changes in APOE expression that are independent of the epsilon genotype have also been described in the AD brain including a recent RNA-Seq analysis that showed upregulation of a rare alternative splice isoform (APOE-005). To replicate these RNA-Seq findings we used quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) to compare APOE-005 and total APOE expression in the superior temporal gyrus of 14 AD cases and 16 neurologically normal controls. In AD, this area shows prominent beta-amyloid deposition but few neurofibrillary tangles and only moderate neuronal loss. As poorer RNA quality among the AD cases was a likely confounder in this study, the analysis was repeated in a RIN-matched sub-cohort of 17 individuals. Contrary to the original RNA-Seq study, we found no difference in total APOE, APOE-005 or the common isoform, APOE-001, between AD cases and controls. Our findings are consistent with ApoE acting largely at the protein level to increase the risk for sporadic AD.

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“…The level of BACE1 in AD pathology is still in argument. Some studies reported that the level of BACE1 was elevated in sporadic AD [1,28], while other investigations showed no obvious changes in mRNA level in spite of the increased BACE1 activity and protein level [20,29,30]. The potential mechanism still needs to be explored.…”

Section: Discussionmentioning

confidence: 97%

Article Withdrawal Statement

2016

International Journal of Neuroscience

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Both senile plaques (SP) and intracellular neurofibrillary tangles (NFT) are important pathological characteristics in Alzheimer's disease (AD). However, the relationship between Aβ deposition and tau hyperphosphorylation is unknown. In this study, increased levels of full-length amyloid precursor protein (APP), APP c terminal fragment (β-CTF), and BACE1 were found in Streptozotocin (STZ)-induced tau hyperphosphorylation models by quantitative polymerase chain reaction (PCR), Western blotting, and immunohistochemistry methods. In previous studies, few strategies focusing on inhibiting β secretase in tau hyperphosphorylation model were utilized. Here, BACE1 RNAi was used to treat the STZ-induced tau hyperphosphorylation animal models. BACE1 RNAi treatment improved the behavior ability of animal models and reduced the amount of Aβ1-40 and Aβ1-42 accompanied by a decrease in the levels of BACE1 and β-CTF. Our results demonstrated that neurological defect and neurotoxic fragments including Aβ and β-CTF were eliminated by BACE1 RNAi in tau hyperphosphorylated model, implying efficiency and safety of BACE1RNAi treatment against AD.

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BACE1 mRNA Expression in Alzheimer's Disease Postmortem Brain Tissue

Cited by 63 publications

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Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

The alternative splicing of the apolipoprotein E gene is unperturbed in the brains of Alzheimer’s disease patients

Article Withdrawal Statement

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