Association studies using novel polymorphisms in BACE1 and BACE2

Nowotny, Petra; Kwon, Jennifer M.; Chakraverty, Sumi; Nowotny, Volker; Morris, John C.; Goate, Alison

doi:10.1097/00001756-200107030-00008

Cited by 39 publications

(47 citation statements)

References 25 publications

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“…Our analysis of BACE1 exon 5 polymorphism did not reveal any association with the risk for AD in both ApoE 4 allele carriers and noncarriers. The positive association results with Caucasians showed that the GG genotype or G allele was the risk factor in ApoE 4 allele carriers [8][9][10] . In the Han Chinese populations, Kan et al [13] reported that the G allele is associated with LOAD (p = 0.02, OR 1.58) and a more significant difference was observed in ApoE 4 allele noncarriers (p = 0.003, OR = 1.91).…”

Section: Discussionmentioning

confidence: 91%

“…A synonymous polymorphism of BACE1 (rs638405) in exon 5 has been reported to be associated with the risk for AD [8][9][10][11][12][13] , but others have failed to find a significant association [14][15][16][17] . After the initial report by Nowotny et al [8] of a weak association with AD in American Caucasians, studies with Spanish [9] , Swiss [10] and German [11] populations also described a similar association of the GG genotype with AD in ApoE 4 allele carriers.…”

Section: Introductionmentioning

confidence: 99%

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Association of BACE1 Gene Polymorphism with Alzheimer’s Disease in Asian Populations: Meta-Analysis Including Korean Samples

Jo¹,

Ahn²,

Kim³

et al. 2008

Dement Geriatr Cogn Disord

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Background: β-Site amyloid precursor protein cleaving enzyme (BACE) is a candidate risk factor for Alzheimer’s disease (AD) from its key role in β-amyloid generation. Previous genetic association studies of BACE1 gene have yielded conflicting results. This study is an attempt to clarify whether the common SNP in exon 5 of BACE1 (rs638405, Val262) is associated with a risk for late-onset AD. Methods: We genotyped a synonymous C/G polymorphism of BACE1 located in exon 5 and apolipoprotein E (ApoE) in 248 AD patients and 224 healthy persons. A meta-analysis with pooled data from four Chinese studies and our results was performed. Results: The allele and genotype frequencies of BACE1 polymorphism were not significantly different between cases and controls (p > 0.05) in the Korean population. A meta-analysis of previously published Asian populations including Koreans showed evidence of a weak association (p = 0.0555 for genotypes, p = 0.0352 for alleles). However, a significant association between the CC genotype and AD was observed in the ApoE-Ε4-positive groups (p = 0.0044, OR = 1.995; 95% CI = 1.319–3.018). Conclusion: These data suggest that BACE1 polymorphism in exon 5 influences risk for late-onset AD in those carrying the ApoE Ε4 allele.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Association of BACE1 Gene Polymorphism with Alzheimer’s Disease in Asian Populations: Meta-Analysis Including Korean Samples

Jo¹,

Ahn²,

Kim³

et al. 2008

Dement Geriatr Cogn Disord

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“…While several studies have reported no significant linkage of BACE1 with Alzheimer's disease (33,34), only weak associations have been identified for several polymorphisms in the BACE1 gene (35). More recently, Gold et al (36) report a significant association of a BACE1 polymorphism for late-onset Alzheimer disease in Apolipoprotein ⑀4 carriers.…”

Section: Figmentioning

confidence: 99%

Altered Amyloid-β Metabolism and Deposition in Genomic-based β-Secretase Transgenic Mice

Chiocco

Kulnane

Younkin

et al. 2004

Journal of Biological Chemistry

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Amyloid-␤ (A␤) the primary component of the senile plaques found in Alzheimer's disease (AD) is generated by the rate-limiting cleavage of amyloid precursor protein (APP) by ␤-secretase followed by ␥-secretase cleavage. Identification of the primary ␤-secretase gene, BACE1, provides a unique opportunity to examine the role this unique aspartyl protease plays in altering A␤ metabolism and deposition that occurs in AD. The current experiments seek to examine how modulating ␤-secretase expression and activity alters APP processing and A␤ metabolism in vivo. Genomic-based BACE1 transgenic mice were generated that overexpress human BACE1 mRNA and protein. The highest expressing BACE1 transgenic line was mated to transgenic mice containing human APP transgenes. Our biochemical and histochemical studies demonstrate that mice overexpressing both BACE1 and APP show specific alterations in APP processing and age-dependent A␤ deposition. We observed elevated levels of A␤ isoforms as well as significant increases of A␤ deposits in these double transgenic animals. In particular, the double transgenics exhibited a unique cortical deposition profile, which is consistent with a significant increase of BACE1 expression in the cortex relative to other brain regions. Elevated BACE1 expression coupled with increased deposition provides functional evidence for ␤-secretase as a primary effector in regional amyloid deposition in the AD brain. Our studies demonstrate, for the first time, that modulation of BACE1 activity may play a significant role in AD pathogenesis in vivo. Alzheimer's disease (AD)1 is a neurodegenerative disease characterized clinically by progressive cognitive impairment (1) and neuropathologically by the presence of senile neuritic plaques and neurofibrillary tangles within the brain. The primary constituent of the senile plaques is amyloid-␤ (A␤) (2), a peptide of 39 -42 amino acids derived from the amyloid precursor protein (APP). A␤ deposition proceeds in a characteristic pattern within the brain with the appearance of plaques first in the basal neocortex, followed by deposition in the frontal cortex, and hippocampal formation until all areas of the cortex contain deposits at end stage AD (3).The generation of A␤ from APP involves three proteases with distinct activities, termed ␣-, ␤-, and ␥-secretase. APP cleavage follows two pathways: cleavage by ␣-secretase generates Cterminal fragment-␣ (CTF-␣), precluding the formation of A␤ upon subsequent ␥-secretase cleavage. Alternatively, cleavage by ␤-secretase at Asp 1 or Glu 11 of the A␤ sequence (4, 5) generates a unique C-terminal membrane-retained fragment, known as CTF-␤. Subsequent cleavage of CTF-␤ by ␥-secretase results in formation of A␤ (for review, see Selkoe, Ref. 6). The Swedish FAD double mutation of APP (7) appears to shift this cleavage pathway to favor processing by ␤-secretase, leading to a significant increase in A␤ production (8, 9).The first APP secretase gene identified was that encoding ␤-secretase (BACE1) (4, 10 -12). BACE1, located on human...

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“…It has been shown that BACE is the major ß-secretase for generation of Aß in neurons [4] and would thus represent the key enzyme initiating the formation of Aß in the brain. However, no mutations or significant polymorphisms in the sequence of BACE gene have been found until now in different populations of AD patients [5][6][7][8][9], although the combination of BACE-specific allele and ApoE4 may slightly increase the risk of AD above that of ApoE4 alone [10]. Nevertheless, inhibition of BACE activity represents an attractive drug target for AD [11], as knockout mice are healthy despite lacking the primary ß-secretase activity in the brain [12].…”

Section: Introductionmentioning

confidence: 99%

Neuronal and Nonneuronal Quantitative BACE Immunocytochemical Expression in the Entorhinohippocampal and Frontal Regions in Alzheimer’s Disease

Leuba¹,

Wernli²,

Vernay³

et al. 2005

Dement Geriatr Cogn Disord

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In this study, we quantitatively investigated the expression of β-site amyloid precursor protein cleaving enzyme (BACE) in the entorhinohippocampal and frontal cortex of Alzheimer’s disease (AD) and old control subjects. The semiquantitative estimation indicated that the intensity of BACE overall immunoreactivity did not differ significantly between AD and controls, but that a significantly stronger staining was observed in the hippocampal regions CA3–4 compared to other regions in both AD patients and controls. The quantitative estimation confirmed that the number of BACE-positive neuronal profiles was not significantly decreased in AD. However, some degeneration of BACE-positive profiles was attested by the colocalization of neurons expressing BACE and exhibiting neurofibrillary tangles (NFT), as well as by a decrease in the surface area of BACE-positive profiles. In addition, BACE immunocytochemical expression was observed in and around senile plaques (SP), as well as in reactive astrocytes. BACE-immunoreactive astrocytes were localized in the vicinity or close to the plaques and their number was significantly increased in AD entorhinal cortex. The higher amount of β-amyloid SP and NFT in AD was not correlated with an increase in BACE immunoreactivity. Taken together, these data accent that AD progression does not require an increased neuronal BACE protein level, but suggest an active role of BACE in immunoreactive astrocytes. Moreover, the strong expression in controls and regions less vulnerable to AD puts forward the probable existence of alternate BACE functions.

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Association studies using novel polymorphisms in BACE1 and BACE2

Cited by 39 publications

References 25 publications

Association of BACE1 Gene Polymorphism with Alzheimer’s Disease in Asian Populations: Meta-Analysis Including Korean Samples

Association of BACE1 Gene Polymorphism with Alzheimer’s Disease in Asian Populations: Meta-Analysis Including Korean Samples

Altered Amyloid-β Metabolism and Deposition in Genomic-based β-Secretase Transgenic Mice

Neuronal and Nonneuronal Quantitative BACE Immunocytochemical Expression in the Entorhinohippocampal and Frontal Regions in Alzheimer’s Disease

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