The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the Down critical region

Acquati, Francesco; Accarino, M.; Nucci, C; Fumagalli, Prisca; Jovine, Luca; Ottolenghi, Sergio; Taramelli, Roberto

doi:10.1016/s0014-5793(00)01192-3

Cited by 122 publications

(100 citation statements)

References 31 publications

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“…Increased beta-secretase activity in DS with age may reflect BACE1 activity [64], but also possibly BACE2, which has approximately a 64% amino acid similarity to BACE1 [1] and is present on chromosome 21 in the DS obligate region [1]. Developmentally, BACE2 protein levels are significantly higher in DS fetal tissue relative to controls [2].…”

Section: Discussionmentioning

confidence: 98%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

107

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Aged individuals with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by the age of 40 years. The purpose of the current study was to measure age-associated changes in APP processing in 36 individuals with DS (5 months-69 years) and in 26 controls (5 months-100 years). Alpha-secretase significantly decreased with age in DS, particularly in cases over the age of 40 years and was stable in controls. The levels of C-terminal fragments of APP reflecting alphasecretase processing (CTF-alpha) decreased with age in both groups. In both groups, there was significant increase in beta-secretase activity with age. CTF-beta remained constant with age in controls suggesting compensatory increases in turnover/clearance mechanisms. In DS, young individuals had the lowest CTF-beta levels that may reflect rapid conversion of beta-amyloid (Aβ) to soluble pools or efficient CTF-beta clearance mechanisms. Treatments to slow or prevent AD in the general population targeting secretase activity may be more efficacious in adults with DS if combined with approaches that enhance Aβ degradation and clearance.

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Section: Discussionmentioning

confidence: 98%

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Nistor

Don

Parekh

et al. 2007

Neurobiology of Aging

107

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“…BACE1 and BACE2 are two highly homologous membranebound aspartyl proteases that can process APP at the ␤-secretase site (1)(2)(3)(4)(5)(6)(7)(8). Although both enzymes exhibit many of the characteristics expected for ␤-secretase, it has been quite convincingly demonstrated that BACE1 is in fact the major ␤-secretase responsible for A␤ generation in brain (9 -11).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

Dominguez

Tournoy

Hartmann

et al. 2005

Journal of Biological Chemistry

326

345

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␤-Secretase (BACE1) is the rate-limiting protease for the generation of the amyloid ␤-peptide (A␤) in Alzheimer disease. Mice in which the bace1 gene is inactivated are reported to be healthy. However, the presence of a homologous gene encoding BACE2 raises the possibility of compensatory mechanisms. Therefore, we have generated bace1, bace2, and double knockout mice. We report here that BACE1 mice display a complex phenotype. A variable but significant number of BACE1 offspring died in the first weeks after birth. The surviving mice remained smaller than their littermate controls and presented a hyperactive behavior. Electrophysiologically, subtle alterations in the steady-state inactivation of voltage-gated sodium channels in BACE1-deficient neurons were observed. In contrast, bace2 knockout mice displayed an overall healthy phenotype. However, a combined deficiency of BACE2 and BACE1 enhanced the bace1 ؊/؊ lethality phenotype. At the biochemical level, we have confirmed that BACE1 deficiency results in an almost complete block of A␤ generation in neurons, but not in glia. As glia are 10 times more abundant in brain compared with neurons, our data indicate that BACE2 could indeed contribute to A␤ generation in the brains of Alzheimer disease and, in particular, Down syndrome patients. In conclusion, our data challenge the general idea of BACE1 as a safe drug target and call for some caution when claiming that no major side effects should be expected from blocking BACE1 activity. Alzheimer disease (AD)1 is the most common cause of dementia for which neither a good diagnostic test nor an effective treatment is available yet. The most widely accepted hypothesis states that AD is initially triggered by the abnormal accumulation and possibly deposition of the small amyloid ␤-peptide (A␤) in different brain regions, which in turn initiates a pathogenic cascade that ultimately leads to neuronal death, AD pathology, and dementia. A␤ is cleaved from a long membranebound precursor, the amyloid precursor protein (APP), by two consecutive cleavages. ␤-and ␥-secretases are the enzymes that liberate the N and C termini of A␤, respectively, and are the subject of intense investigation because of their relevance as candidate therapeutic targets to treat AD.BACE1 and BACE2 are two highly homologous membranebound aspartyl proteases that can process APP at the ␤-secretase site (1-8). Although both enzymes exhibit many of the characteristics expected for ␤-secretase, it has been quite convincingly demonstrated that BACE1 is in fact the major ␤-secretase responsible for A␤ generation in brain (9 -11). Contrary to BACE1, BACE2 is more highly expressed in peripheral tissues, but also to some extent in brain (2,8,12,13), raising the question of whether BACE2 could contribute to the generation of the brain A␤ pool. Both BACE1 and BACE2 can cleave APP in vitro not only at Asp 1 (numbering considering the first amino acid of A␤ as position 1), but also at internal sites within the A␤ region. BACE1 cleaves between amino acids 10 and 11 o...

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“…BACE1 knock-out mice completely lack A␤ production in the brain (14,15), indicating that BACE1 carries majority of ␤-secretase activity in the brain. BACE2 may be important in Down syndrome pathology, because the enzyme is encoded by chromosome 21 (12) and its expression is elevated in trisomic brains (16).…”

Section: A Characteristic Feature Of Alzheimer Disease (Ad)mentioning

confidence: 99%

In Vivo Cleavage of α2,6-Sialyltransferase by Alzheimer β-Secretase

Kitazume

Nakagawa

Oka

et al. 2005

Journal of Biological Chemistry

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␤-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is a membrane-bound aspartic protease that cleaves amyloid precursor protein to produce a neurotoxic peptide, A␤, and is implicated in triggering the pathogenesis of Alzheimer disease. We previously reported that BACE1 cleaved rat ␤-galactoside ␣2,6-sialyltransferase (ST6Gal I) that was overexpressed in COS cells and that the NH 2 terminus of ST6Gal I secreted from the cells (E41 form) was Glu 41 . Here we report that BACE1 gene knock-out mice have one third as much plasma ST6Gal I as control mice, indicating that BACE1 is a major protease which is responsible for cleaving ST6Gal I in vivo. We also found that BACE1-transgenic mice have increased level of ST6Gal I in plasma. Secretion of ST6Gal I from the liver into the plasma is known to be up-regulated during the acute-phase response. To investigate the role of BACE1 in ST6Gal I secretion in vivo, we analyzed the levels of BACE1 mRNA in the liver, as well as the plasma levels of ST6Gal I, in a hepatopathological model, i.e. Long-Evans Cinnamon (LEC) rats. This rat is a mutant that spontaneously accumulates copper in the liver and incurs hepatic damage. LEC rats exhibited simultaneous increases in BACE1 mRNA in the liver and in the E41 form of the ST6Gal I protein, the BACE1 product, in plasma as early as 6 weeks of age, again suggesting that BACE1 cleaves ST6Gal I in vivo and controls the secretion of the E41 form.

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The gene encoding DRAP (BACE2), a glycosylated transmembrane protein of the aspartic protease family, maps to the Down critical region

Cited by 122 publications

References 31 publications

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Alpha- and beta-secretase activity as a function of age and beta-amyloid in Down syndrome and normal brain

Phenotypic and Biochemical Analyses of BACE1- and BACE2-deficient Mice

In Vivo Cleavage of α2,6-Sialyltransferase by Alzheimer β-Secretase

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