A Splice Variant of β-Secretase Deficient in the Amyloidogenic Processing of the Amyloid Precursor Protein

Bodendorf, Ursula; Fischer, Frauke; Bodian, Dale L.; Multhaup, Gerd; Paganetti, Paolo

doi:10.1074/jbc.m008861200

Cited by 75 publications

(75 citation statements)

References 21 publications

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“…The BACE1 gene is composed of nine exons, and its pre-mRNA was previously found to undergo alternative splicing (25)(26)(27). BACE1 mRNA is most highly expressed in brain and pancreas (5)(6)(7)(8)(9), and alternatively spliced transcripts of BACE1 have been identified in both tissues (26,27).…”

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“…The activities of BACE1 protein isoforms produced by alternative splicing are not well established. Past studies suggest that BACE1 476 and BACE1 457 have reduced activity or are completely inactive against APP, although the activities of BACE1 476, BACE1 457, and BACE1 432 have never been measured directly and the issue remains largely unresolved (25)(26)(27).Because BACE1 occupies such an important position in the pathway toward A␤ generation and BACE1 alternative splicing could produce changes in overall ␤-secretase activity, a comprehensive and systematic investigation of this splicing event is necessary. In this study, we quantified the relative levels of BACE1 alternatively spliced transcripts using real-time PCR,…”

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Promotion of BACE1 mRNA Alternative Splicing Reduces Amyloid β-Peptide Production

Mowrer

Wolfe

2008

Journal of Biological Chemistry

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Production of the amyloid ␤-peptide (A␤) via sequential proteolytic cleavage of the amyloid precursor protein by ␤-and ␥-secretases is strongly implicated in the pathogenesis of Alzheimer disease. The ␤-secretase that executes the first cleavage event is a transmembrane aspartyl protease known as ␤-site amyloid precursor protein-cleaving enzyme 1 (BACE1). BACE1 pre-mRNA is alternatively spliced through the use of alternative splice sites in exons 3 and 4, although the significance of these splicing events is unclear. Here, we quantitatively measured relative levels of BACE1 transcripts and identified a novel splice variant of BACE1. We found a subtle but significant difference in BACE1 splicing between brain and pancreas, indicating the cellular environment can affect BACE1 alternative splicing. Furthermore, we have shown that BACE1 proteins translated from alternatively spliced transcripts have dramatically reduced ␤-secretase activity and promotion of BACE1 alternative splicing reduces A␤ production. These findings illustrate the importance of BACE1 alternative splicing in affecting the level of A␤ produced in cells and suggest that targeting regulation of BACE1 alternative splicing is a potential therapeutic strategy for lowering ␤-secretase activity.Deposition of extracellular plaques in the brain is a hallmark of Alzheimer disease (AD) 2 pathology. The major component of these plaques is the amyloid ␤-peptide (A␤), a hydrophobic peptide usually 40 or 42 amino acids in length and prone to aggregation (1, 2). A␤ is produced by sequential proteolysis of the amyloid precursor protein (APP) by ␤-and ␥-secretases (3, 4). ␤-site APP-cleaving enzyme 1 (BACE1) is the primary transmembrane aspartyl protease responsible for ␤-secretase activity in the brain and carries out the first cleavage step leading to A␤ production (5-9). Moreover, BACE1 protein and activity levels are elevated in AD brains relative to controls, further suggesting its involvement in AD pathogenesis (10 -14).Elimination or reduction of BACE1 activity in order to slow A␤ production is an attractive therapeutic strategy for AD. Although the brains of Bace1 knock-out mice do not produce A␤ and these mice appear relatively healthy (15-17), there is evidence that complete absence of BACE1 may cause reduced myelination as well as some cognitive deficits in mice (18 -20). However, partial reduction of BACE1 has been shown to dramatically reduce plaque deposition and synaptic deficits in APP transgenic mouse models (20 -22). Although a number of BACE1 inhibitors have been developed, identification of a selective compound that is potent in vivo and practical for clinical development has proven challenging (23, 24).The BACE1 gene is composed of nine exons, and its pre-mRNA was previously found to undergo alternative splicing (25-27). BACE1 mRNA is most highly expressed in brain and pancreas (5-9), and alternatively spliced transcripts of BACE1 have been identified in both tissues (26,27). Normal splicing of BACE1 results in production of the full-length 50...

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Promotion of BACE1 mRNA Alternative Splicing Reduces Amyloid β-Peptide Production

Mowrer

Wolfe

2008

Journal of Biological Chemistry

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“…To obtain pSVHACPY, the gene for the wild-type enzyme, the BglII-BsuI fragment containing the point mutation (G255R) was cut out and replaced by the BglII-BsuI fragment obtained from PCR on wild-type yeast genomic DNA. Plasmids for expression of BACE457⌬ and HA-tagged EDEM are described elsewhere (23,34).…”

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“…Anti-Golgi mannosidase II and anti-p58 were supplied by Dr. K. W. Moremen (University of Georgia, Athens, GA) and Dr. J. Saraste (University of Bergen, Bergen, Norway), respectively. Rabbit anti-calnexin, anti-CPY, and anti-BACE457⌬ sera have been described elsewhere (15,(32)(33)(34).…”

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Multiple Endoplasmic Reticulum-associated Pathways Degrade Mutant Yeast Carboxypeptidase Y in Mammalian Cells

Mancini

Aebi

Helenius

2003

Journal of Biological Chemistry

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The degradation of misfolded and unassembled proteins by the endoplasmic reticulum (ER)-associated degradation (ERAD) has been shown to occur mainly through the ubiquitin-proteasome pathway after transport of the protein to the cytosol. Recent work has revealed a role for N-linked glycans in targeting aberrant glycoproteins to ERAD. To further characterize the molecular basis of substrate recognition and sorting during ERAD in mammalian cells, we expressed a mutant yeast carboxypeptidase Y (CPY*) in CHO cells. CPY* was retained in the ER in un-aggregated form, and degraded after a 45-min lag period. Degradation was predominantly by a proteasome-independent, non-lysosomal pathway. The inhibitor of ER mannosidase I, kifunensine, blocked the degradation by the alternate pathway but did not affect the proteasomal fraction of degradation. Upon inhibition of glucose trimming, the initial lag period was eliminated and degradation thus accelerated. Our results indicated that, although the proteasome is a major player in ERAD, alternative routes are present in mammalian cells and can play an important role in the disposal of both glycoproteins and non-glycoproteins.

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β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease

Fukumoto

Cheung²,

Hyman³

et al. 2002

Arch Neurol

645

494

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A Splice Variant of β-Secretase Deficient in the Amyloidogenic Processing of the Amyloid Precursor Protein

Cited by 75 publications

References 21 publications

Promotion of BACE1 mRNA Alternative Splicing Reduces Amyloid β-Peptide Production

Promotion of BACE1 mRNA Alternative Splicing Reduces Amyloid β-Peptide Production

Multiple Endoplasmic Reticulum-associated Pathways Degrade Mutant Yeast Carboxypeptidase Y in Mammalian Cells

β-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease

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