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

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.

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

BioMolecular Concepts ◽

10.1515/bmc-2014-0041 ◽

2015 ◽

Vol 6 (1) ◽

pp. 11-32 ◽

Cited By ~ 12

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.

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

Journal of Biological Chemistry ◽

10.1074/jbc.m706024200 ◽

2007 ◽

Vol 282 (46) ◽

pp. 33313-33325 ◽

Cited By ~ 15

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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Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00255.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. R585-R593 ◽

Cited By ~ 8

Author(s):

Rebecca E. K. MacPherson

Keyword(s):

Insulin Resistance ◽

Amyloid Precursor Protein ◽

Significant Risk ◽

Precursor Protein ◽

Amyloid Peptide ◽

Amyloid Precursor Protein Processing ◽

Direct Effects ◽

App Processing ◽

Β Amyloid ◽

Exercise Induced

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer’s disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

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Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

10.1101/616540 ◽

2019 ◽

Author(s):

Tatiana Burrinha ◽

Ricardo Gomes ◽

Ana Paula Terrasso ◽

Cláudia Guimas Almeida

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Precursor Protein ◽

App Processing ◽

Early Endosomes ◽

Primary Mouse ◽

Β Amyloid ◽

Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

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