Enhancement of proteolytic processing of the β-amyloid precursor protein by hyperforin

2003 ◽  
Vol 66 (11) ◽  
pp. 2177-2184 ◽  
Author(s):  
Bettina Froestl ◽  
Barbara Steiner ◽  
Walter E. Müller
Keyword(s):  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Β Amyloid

scholarly journals Transcriptional Regulation of BACE1, the β-Amyloid Precursor Protein β-Secretase, by Sp1

2004 ◽  
Vol 24 (2) ◽  
pp. 865-874 ◽  
Author(s):  
Michelle A. Christensen ◽  
Weihui Zhou ◽  
Hong Qing ◽  
Anna Lehman ◽  
Sjaak Philipsen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Transcriptional Level ◽  
Response Element ◽  
App Processing ◽  
Transcription Factor Sp1 ◽  
Β Amyloid

ABSTRACT Proteolytic processing of the β-amyloid precursor protein (APP) at the β site is essential to generate Aβ. BACE1, the major β-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human BACE1 gene and identified key regions necessary for promoter activity. BACE1 gene expression is controlled by a TATA-less promoter. The region of bp −619 to +46 is the minimal promoter to control the transcription of the BACE1 gene. Several putative cis-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5′ flanking region of the BACE1 gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate Aβ. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that BACE1 gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating Aβ in Alzheimer's disease.

scholarly journals Proteolytic processing of Alzheimer’s β-amyloid precursor protein

2011 ◽  
Vol 120 ◽  
pp. 9-21 ◽  
Author(s):  
Han Zhang ◽  
Qilin Ma ◽  
Yun-wu Zhang ◽  
Huaxi Xu
Keyword(s):  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Β Amyloid

scholarly journals The cholesterol transporter ABCG1 modulates the subcellular distribution and proteolytic processing of β-amyloid precursor protein

2007 ◽  
Vol 48 (5) ◽  
pp. 1022-1034 ◽  
Author(s):  
Gavin H. Tansley ◽  
Braydon L. Burgess ◽  
Matt T. Bryan ◽  
Yuan Su ◽  
Veronica Hirsch-Reinshagen ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Subcellular Distribution ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Β Amyloid

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

2015 ◽  
Vol 6 (1) ◽  
pp. 11-32 ◽  
Author(s):  
Khue Vu Nguyen
Keyword(s):  
Amyloid Precursor Protein ◽  
Late Onset ◽  
Expression Patterns ◽  
Complex Molecule ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Onset Age ◽  
Mrna Isoforms ◽  
App Processing ◽  
Β Amyloid

AbstractBeta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer’s disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age <65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age >65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APP-mRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

scholarly journals Presenilin 1 Negatively Regulates β-Catenin/T Cell Factor/Lymphoid Enhancer Factor-1 Signaling Independently of β-Amyloid Precursor Protein and Notch Processing

2001 ◽  
Vol 152 (4) ◽  
pp. 785-794 ◽  
Author(s):  
Salvador Soriano ◽  
David E. Kang ◽  
Maofu Fu ◽  
Richard Pestell ◽  
Nathalie Chevallier ◽  
...  
Keyword(s):  
T Cell ◽  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Presenilin 1 ◽  
Dependent Manner ◽  
Notch 1 ◽  
T Cell Factor ◽  
Β Amyloid ◽  
Enhancer Factor

In addition to its documented role in the proteolytic processing of Notch-1 and the β-amyloid precursor protein, presenilin 1 (PS1) associates with β-catenin. In this study, we show that this interaction plays a critical role in regulating β-catenin/T Cell Factor/Lymphoid Enhancer Factor-1 (LEF) signaling. PS1 deficiency results in accumulation of cytosolic β-catenin, leading to a β-catenin/LEF-dependent increase in cyclin D1 transcription and accelerated entry into the S phase of the cell cycle. Conversely, PS1 specifically represses LEF-dependent transcription in a dose-dependent manner. The hyperproliferative response can be reversed by reintroducing PS1 expression or overexpressing axin, but not a PS1 mutant that does not bind β-catenin (PS1Δcat) or by two different familial Alzheimer's disease mutants. In contrast, PS1Δcat restores Notch-1 proteolytic cleavage and Aβ generation in PS1-deficient cells, indicating that PS1 function in modulating β-catenin levels can be separated from its roles in facilitating γ-secretase cleavage of β-amyloid precursor protein and in Notch-1 signaling. Finally, we show an altered response to Wnt signaling and impaired ubiquitination of β-catenin in the absence of PS1, a phenotype that may account for the increased stability in PS1-deficient cells. Thus, PS1 adds to the molecules that are known to regulate the rapid turnover of β-catenin.

scholarly journals Fe65 Stimulates Proteolytic Liberation of the β-Amyloid Precursor Protein Intracellular Domain

2007 ◽  
Vol 282 (46) ◽  
pp. 33313-33325 ◽  
Author(s):  
Jesse C. Wiley ◽  
Elise A. Smith ◽  
Mark P. Hudson ◽  
Warren C. Ladiges ◽  
Mark Bothwell
Keyword(s):  
Amyloid Precursor Protein ◽  
Proteolytic Processing ◽  
Precursor Protein ◽  
Direct Stimulation ◽  
Intracellular Domain ◽  
App Processing ◽  
Nuclear Signaling ◽  
Enhanced Production ◽  
Β Amyloid ◽  
Stimulation Of

The β-amyloid precursor protein (APP)-binding protein Fe65 is involved in APP nuclear signaling and several steps in APP proteolytic processing. In this study, we show that Fe65 stimulates γ-secretase-mediated liberation of the APP intracellular domain (AICD). The mechanism of Fe65-mediated stimulation of AICD formation appears to be through enhanced production of the carboxyl-terminal fragment substrates of γ-secretase and direct stimulation of processing by γ-secretase. The stimulatory capacity of Fe65 is isoform-dependent, as the non-neuronal and a2 isoforms promote APP processing more effectively than the exon 9 inclusive neuronal form of Fe65. Intriguingly, Fe65 stimulation of AICD production appears to be inversely related to pathogenic β-amyloid production as the Fe65 isoforms profoundly stimulate AICD production and simultaneously decrease Aβ42 production. Despite the capacity of Fe65 to stimulate γ-secretase-mediated APP proteolysis, it does not rescue the loss of proteolytic function associated with the presenilin-1 familial Alzheimer disease mutations. These data suggest that Fe65 regulation of APP proteolysis may be integrally associated with its nuclear signaling function, as all antecedent proteolytic steps prior to release of Fe65 from the membrane are fostered by the APP-Fe65 interaction.

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