BACE1 Expression and Activity: Relevance in Alzheimer’s Disease

Zacchetti, Daniele; Chieregatti, Evelina; Bettegazzi, Barbara; Mihailovich, Marija; Sousa, Vitor; Grohovaz, Fabio; Meldolesi, Jacopo

doi:10.1159/000101836

Cited by 19 publications

(17 citation statements)

References 203 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…YY2 is highly similar to the evolutionarily well-conserved zinc finger gene YY1 [38], which activates beta-site amyloid precursor protein-cleaving enzyme 1 ( BACE1 ) expression [39]. BACE1 , which was present in the list of 271 genes between HIPnet and MTGnet, is necessary for the generation of beta-amyloid peptides, the principal constituents of senile plaques, in AD subjects [40,41]. Toll-like receptor 4 ( TLR4 ) signalling pathway has been implicated in the clearance of beta amyloid deposits in the brain of Alzheimer's disease subjects [42,43].…”

Section: Results and Conclusionmentioning

confidence: 99%

Analysis of Alzheimer's disease severity across brain regions by topological analysis of gene co-expression networks

Ray

Zhang

2010

BMC Syst Biol

View full text Add to dashboard Cite

BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative disorder involving variations in the transcriptome of many genes. AD does not affect all brain regions simultaneously. Identifying the differences among the affected regions may shed more light onto the disease progression. We developed a novel method involving the differential topology of gene coexpression networks to understand the association among affected regions and disease severity.MethodsWe analysed microarray data of four regions - entorhinal cortex (EC), hippocampus (HIP), posterior cingulate cortex (PCC) and middle temporal gyrus (MTG) from AD affected and normal subjects. A coexpression network was built for each region and the topological overlap between them was examined. Genes with zero topological overlap between two region-specific networks were used to characterise the differences between the two regions.Results and conclusionResults indicate that MTG shows early AD pathology compared to the other regions. We postulate that if the MTG gets affected later in the disease, post-mortem analyses of individuals with end-stage AD will show signs of early AD in the MTG, while the EC, HIP and PCC will have severe pathology. Such knowledge is useful for data collection in clinical studies where sample selection is a limiting factor as well as highlighting the underlying biology of disease progression.

show abstract

Section: Results and Conclusionmentioning

confidence: 99%

Analysis of Alzheimer's disease severity across brain regions by topological analysis of gene co-expression networks

Ray

Zhang

2010

BMC Syst Biol

View full text Add to dashboard Cite

show abstract

“…BACE1/␤-secretase can become expressed in both cell types (32,(35)(36)(37), and increased BACE1 expression can be observed in neurons and glia in AD patients and in AD mouse models (35,(37)(38)(39). Although neurons and glia can theoretically contribute to A␤ load in the brain, further work is now needed to address the cell-type specificity of the observed effects of miR-29a/b-1 on BACE1 expression in vivo.…”

Section: Figmentioning

confidence: 99%

Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression

Hébert

Horré

Nicolaï

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

1,041

951

View full text Add to dashboard Cite

Although the role of APP and PSEN genes in genetic Alzheimer's disease (AD) cases is well established, fairly little is known about the molecular mechanisms affecting A␤ generation in sporadic AD. Deficiency in A␤ clearance is certainly a possibility, but increased expression of proteins like APP or BACE1/␤-secretase may also be associated with the disease. We therefore investigated changes in microRNA (miRNA) expression profiles of sporadic AD patients and found that several miRNAs potentially involved in the regulation of APP and BACE1 expression appeared to be decreased in diseased brain. We show here that miR-29a, -29b-1, and -9 can regulate BACE1 expression in vitro. The miR-29a/b-1 cluster was significantly (and AD-dementia-specific) decreased in AD patients displaying abnormally high BACE1 protein. Similar correlations between expression of this cluster and BACE1 were found during brain development and in primary neuronal cultures. Finally, we provide evidence for a potential causal relationship between miR-29a/b-1 expression and A␤ generation in a cell culture model. We propose that loss of specific miRNAs can contribute to increased BACE1 and A␤ levels in sporadic AD.neurodegeneration ͉ amyloid ͉ noncoding RNA M utations in the APP and PSEN genes cause A␤ accumulation and familial Alzheimer's disease (AD) (1-4). However, little is known about the mechanisms that contribute to A␤ accumulation in the vast majority of sporadic AD cases. BACE1/␤-secretase cleavage of APP is the rate-limiting step for A␤ peptide production. Increased BACE1 expression is observed in patients with sporadic AD (5-8), and several mechanisms for this up-regulation have been proposed (9, 10). A link between BACE1 levels, A␤ load, and AD pathology has been reported (11), suggesting that increased BACE1 expression is indeed an important risk factor for sporadic AD.miRNAs are small noncoding RNAs that control gene expression at the posttranscriptional level by binding to the 3Ј untranslated region (3ЈUTR) of target mRNAs leading to their translational inhibition or sometimes degradation. Several miRNAs are specifically expressed or enriched in the brain (12-15), and some have been associated with neuronal differentiation, synaptic plasticity, and memory formation (16,17). The hypothesis that miRNA pathways could contribute to neurodegeneration is appealing (18) and has been tested to a certain degree in Drosophila (19) and mouse models (18,20,21) in which all miRNAs are lacking. Recently, Kim et al. (21) identified a subgroup of miRNAs, normally enriched in the midbrain, which expression is altered in sporadic Parkinson's disease (PD). One of the affected miRNAs, miR-133b, controls the differentiation and function of dopaminergic neurons (which are lost in PD). Here, we sought to investigate whether changes in miRNA expression exist in sporadic AD, and whether these changes could contribute to A␤ pathology. ResultsmiRNA Profile Analysis of Sporadic AD Brain. In a pilot study, we assessed the expression profiles of 328 human miRNAs f...

show abstract

“…Oxidative stress induces BACE1 transcription [22], thereby promoting the production of Aβ [23]. Aβ has iron chelating sites [24], thus protecting the cells from oxidative stress.…”

Section: Introductionmentioning

confidence: 99%

Altered APP Carboxyl-Terminal Processing Under Ferrous Iron Treatment in PC12 Cells

Kim

Yoo

2013

Korean J Physiol Pharmacol

View full text Add to dashboard Cite

Amyloid-β peptide (Aβ), generated by proteolytic cleavage of the amyloid precursor protein (APP), plays a pivotal role in the pathogenesis of Alzheimer's disease (AD). The key step in the generation of Aβ is cleavage of APP by beta-site APP-cleaving enzyme 1 (BACE1). Levels of BACE1 are increased in vulnerable regions of the AD brain, but the underlying mechanism is unknown. In the present study, we reported the effects of ferrous ions at subtoxic concentrations on the mRNA levels of BACE1 and a-disintegrin-and-metalloproteinase 10 (ADAM10) in PC12 cells and the cell responses to ferrous ions. The cell survival in PC12 cells significantly decreased with 0 to 0.3 mM FeCl2, with 0.6 mM FeCl2 treatment resulting in significant reductions by about 75%. 4,6-diamidino-2-phenylindole (DAPI) staining showed that the nuclei appeared fragmented in 0.2 and 0.3 mM FeCl2. APP-α-carboxyl terminal fragment (APP-α-CTF) associations with ADAM10 and APP-β-CTF with BACE1 were increased. Levels of ADAM10 and BACE1 mRNA increased in response to the concentrations of 0.25 mM, respectively. In addition, p-ERK and p-Bad (S112, S155) expressions were increased, suggesting that APP-CTF formation is related to ADAM10/BACE1 expression. Levels of Bcl-2 protein were increased, but significant changes were not observed in the expression of Bax. These data suggest that ion-induced enhanced expression of AMDA10/BACE1 could be one of the causes for APP-α/β-CTF activation.

show abstract

BACE1 Expression and Activity: Relevance in Alzheimer’s Disease

Cited by 19 publications

References 203 publications

Analysis of Alzheimer's disease severity across brain regions by topological analysis of gene co-expression networks

Analysis of Alzheimer's disease severity across brain regions by topological analysis of gene co-expression networks

Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression

Altered APP Carboxyl-Terminal Processing Under Ferrous Iron Treatment in PC12 Cells

Contact Info

Product

Resources

About