NSAIDs repress BACE1 gene promoter activity by activation of PPARgamma

Sastre, Magdalena; Rößner, Steffen; Bogdanović, Nebojša; Rosen, Evan D.; Dewachter, Ilse; Borghgraef, P.; Evert, Bernd O.; Dumitrescu-Ozimek, Lucia; Thal, D.; Landreth, Gary E.; Walter, Jörn; Klockgether, Thomas; Leuven, Fred Van; Heneka, M. T.

doi:10.1055/s-2005-919211

Cited by 11 publications

(20 citation statements)

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“…The effect of FGF2 on BACE1 transcription could be mediated through the binding of FGF2 to FGF receptor 1, the main receptor for FGF2 in hippocampus, whose signaling cascade involves the association of transcriptional coactivator CPB/p300 (Woodbury and Ikezu, 2014) with transcription factors such as nuclear factor kappa B (Zhong et al, 1998) and peroxisome proliferator-activated gamma receptor (Puigserver et al, 1999). Interestingly, BACE1 promoter contains consensus sites for both nuclear factor kappa B and peroxisome proliferator-activated gamma receptor Sastre et al, 2006). FGF2 could also produce beneficial effects in neurodegenerative diseases through its anti-inflammatory properties.…”

Section: Discussionmentioning

confidence: 97%

Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice

Katsouri

Ashraf

Birch

et al. 2015

Neurobiology of Aging

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Section: Discussionmentioning

confidence: 97%

Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice

Katsouri

Ashraf

Birch

et al. 2015

Neurobiology of Aging

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“…Certain pro-inflammatory molecules can elevate astrocytic Bace1 expression (38), and Bace1 levels appear to rise at sites of glial activation prior to plaque development (39). Interestingly, long-term nonsteroidal anti-inflammatory drug use reduces AD risk, an effect that may be mediated in part by activation of peroxisome proliferator-activated receptor-␥ and subsequent repression of BACE1 promoter activity (40).…”

Section: Bace1 Gene Expressionmentioning

confidence: 99%

The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology

Cole

Vassar

2008

Journal of Biological Chemistry

230

160

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Amyloid plaques, composed of the amyloid ␤-protein (A␤), are hallmark neuropathological lesions in Alzheimer disease (AD) brain. A␤ fulfills a central role in AD pathogenesis, and reduction of A␤ levels should prove beneficial for AD treatment. A␤ generation is initiated by proteolysis of amyloid precursor protein (APP) by the ␤-secretase enzyme BACE1. Bace1 knockout (Bace1 ؊/؊ ) mice have validated BACE1 as the authentic ␤-secretase in vivo. BACE1 is essential for A␤ generation and represents a suitable drug target for AD therapy, especially because this enzyme is up-regulated in AD. However, although initial data indicated that Bace1 ؊/؊ mice lack an overt phenotype, the BACE1-mediated processing of APP and other substrates may be important for specific biological processes. In this minireview, topics range from the initial identification of BACE1 to the fundamental knowledge gaps that remain in our understanding of this protease. We address pertinent questions such as putative causes of BACE1 elevation in AD and discuss why, nine years since the identification of BACE1, treatments that address the underlying pathological mechanisms of AD are still lacking. Alzheimer Disease AD2 is the most common form of dementia, afflicting over 29 million people worldwide, a figure anticipated to rise exponentially within decades. Although the etiology remains enigmatic, AD appears to be brought about by both genetic and non-genetic factors. ϳ5% of AD cases are familial (FAD), caused by autosomal dominant mutations in either APP or the PS genes. The underlying cause(s) remain elusive for the majority of sporadic AD cases, although specific risk factors have been identified and include aging, the apolipoprotein E4 allele, certain vascular diseases, and TBI (1).Several major pathologies are observed in AD, and the amyloid hypothesis states that A␤ plays a critical early role, triggering a complex pathological cascade that leads to neurodegeneration (2). A strong genetic correlation exists between FAD and a neurotoxic form of fibrillogenic A␤, A␤42 (3). Pre-symptomatic FAD patients exhibit A␤42 elevations or elevations in A␤42 levels relative to levels of the less fibrillogenic peptide, A␤40, indicating that A␤42 may initiate pathophysiology. Patients with additional copies of the APP gene exhibit total A␤ overproduction and develop early-onset AD (1, 4). Data point toward a critical role for A␤42 in AD etiology, and strategies to lower brain A␤42 levels should be therapeutically beneficial in AD. A␤ GenerationA␤ is formed from endoproteolysis of APP, a type 1 membrane protein (Fig. 1) (5). BACE1 (␤-site APP-cleaving enzyme 1) is essential for initiating A␤ generation and cleaves the APP Asp ϩ1 residue to form the A␤ N terminus, APPs␤, and a C-terminal fragment, C99. BACE1 cleavage of APP is a prerequisite for ␥-secretase-mediated cleavage, and C99 is proteolyzed by ␥-secretase (a protein complex containing PS), which generates an AICD and A␤. This imprecise cleavage produces A␤ variants, including those ending at residues 40 ...

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“…In addition, delivering inhibitory small molecules across the cell membrane and blood-brain barrier poses another difficulty. Recently, the BACE1 promoter was defined, and several transcription factors regulating BACE1 expression identified, including SP1 (16), PPAR␥ (17), and Yin Yang 1 (YY1) (18). Interestingly, protein levels of BACE1 and some of these transcription factors have been found altered in AD brain regions containing A␤ plaques, suggesting that increased BACE1 expression resulting from altered levels of its transcriptional activators may contribute in part to AD pathogenesis (17)(18)(19)(20).…”

mentioning

confidence: 99%

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

Zhang

Zhou

Wang

et al. 2007

Journal of Biological Chemistry

381

294

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The incidence of Alzheimer disease (AD) and vascular dementia is greatly increased following cerebral ischemia and stroke in which hypoxic conditions occur in affected brain areas. ␤-Amyloid peptide (A␤), which is derived from the ␤-amyloid precursor protein (APP) by sequential proteolytic cleavages from ␤-secretase (BACE1) and presenilin-1 (PS1)/␥-secretase, is widely believed to trigger a cascade of pathological events culminating in AD and vascular dementia. However, a direct molecular link between hypoxic insults and APP processing has yet to be established. Here, we demonstrate that acute hypoxia increases the expression and the enzymatic activity of BACE1 by up-regulating the level of BACE1 mRNA, resulting in increases in the APP C-terminal fragment-␤ (␤CTF) and A␤. Hypoxia has no effect on the level of PS1, APP, and tumor necrosis factor-␣-converting enzyme (TACE, an enzyme known to cleave APP at the ␣-secretase cleavage site). Sequence analysis, mutagenesis, and gel shift studies revealed binding of HIF-1 to the BACE1 promoter. Overexpression of HIF-1␣ increases BACE1 mRNA and protein level, whereas down-regulation of HIF-1␣ reduced the level of BACE1. Hypoxic treatment fails to further potentiate the stimulatory effect of HIF-1␣ overexpression on BACE1 expression, suggesting that hypoxic induction of BACE1 expression is primarily mediated by HIF-1␣. Finally, we observed significant reduction in BACE1 protein levels in the hippocampus and the cortex of HIF-1␣ conditional knock-out mice. Our results demonstrate an important role for hypoxia/HIF-1␣ in modulating the amyloidogenic processing of APP and provide a molecular mechanism for increased incidence of AD following cerebral ischemic and stroke injuries.An important pathologic feature of Alzheimer disease (AD) 4 is formation of extracellular senile plaques in the brain, whose major components are small peptides called ␤-amyloid (A␤) derived from ␤-amyloid precursor protein (APP). APP is sequentially cleaved first by the ␤-secretase (␤-site amyloid precursor protein cleaving enzyme, BACE) and then by the ␥-secretase complex (including presenilin, nicastrin, APH-1, and PEN-2) to generate the heterogeneous A␤ species, mostly A␤40 but also the more deleterious A␤42. Alternatively, APP can be cleaved by ␣-secretase within the A␤ domain to generate non-amyloidogenic soluble APP␣ (sAPP␣) (1-3). The exact ␣-secretase is not known, but a disintegrin and metalloprotease domain 10 (ADAM10) and TNF-␣-converting enzyme (TACE) are two likely candidates (4, 5). It is widely believed that A␤ overproduction directly or indirectly initiates a cascade of neurodegenerative steps resulting in formation of senile plaques, neurofibrillary tangles, and neuronal loss, which characterize AD (6). Hence analysis of cellular regulation affecting A␤ generation, including identification of factors regulating the level/ activity of APP cleavage enzymes, should provide invaluable information for AD therapeutic intervention.BACE is a membrane-bound aspartic protease whose activity is t...

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NSAIDs repress BACE1 gene promoter activity by activation of PPARgamma

Cited by 11 publications

References 0 publications

Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice

Systemic administration of fibroblast growth factor-2 (FGF2) reduces BACE1 expression and amyloid pathology in APP23 mice

The Role of Amyloid Precursor Protein Processing by BACE1, the β-Secretase, in Alzheimer Disease Pathophysiology

Hypoxia-inducible Factor 1α (HIF-1α)-mediated Hypoxia Increases BACE1 Expression and β-Amyloid Generation

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