Dimerization of β-Site β-Amyloid Precursor Protein-cleaving Enzyme

Westmeyer, Gil G.; Willem, Michael; Lichtenthaler, Stefan F.; Lurman, Glenn; Multhaup, Gerd; Assfalg-Machleidt, Irmgard; Reiß, Karina; Säftig, Paul; Haass, Christian

doi:10.1074/jbc.m410378200

Cited by 104 publications

(104 citation statements)

References 67 publications

(75 reference statements)

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“…6) (our unpublished observations). Furthermore, it has been reported that full-length BACE1, forming a high-molecular-weight complex associated with lipid, exhibits higher enzymatic activity than that of C-terminally truncated BACE1 (1-454) (Marlow et al, 2003;Westmeyer et al, 2004). This may support the view that lipophilic TAK-070 effectively reaches the membrane-associated BACE1 complex.…”

Section: Discussionsupporting

confidence: 74%

A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

Fukumoto

Takahashi²,

Tarui³

et al. 2010

J. Neurosci.

121

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We discovered a nonpeptidic compound, TAK-070, that inhibited BACE1, a rate-limiting protease for the generation of A␤ peptides that are considered causative for Alzheimer's disease (AD), in a noncompetitive manner. TAK-070 bound to full-length BACE1, but not to truncated BACE1 lacking the transmembrane domain. Short-term oral administration of TAK-070 decreased the brain levels of soluble A␤, increased that of neurotrophic sAPP␣ by ϳ20%, and normalized the behavioral impairments in cognitive tests in Tg2576 mice, an APP transgenic mouse model of AD. Six-month chronic treatment decreased cerebral A␤ deposition by ϳ60%, preserving the pharmacological efficacy on soluble A␤ and sAPP␣ levels. These results support the feasibility of BACE1 inhibition with a noncompetitive inhibitor as disease-modifying as well as symptomatic therapy for AD.

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Section: Discussionsupporting

confidence: 74%

A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

Fukumoto

Takahashi²,

Tarui³

et al. 2010

J. Neurosci.

121

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“…BACE1 was cotransfected with either control vector or TMEM59 into HEK293 cells. In control cells BACE1 was mainly present in a mature and to a low extent in an immature form, in agreement with previous publications (58,59). The mature form is complex N-glycosylated and resistant to treatment with endoglycosidase H, which only removes N-linked sugars that are not complex glycosylated (Fig.…”

Section: Tmem59supporting

confidence: 79%

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Ullrich

Münch

Neumann

et al. 2010

Journal of Biological Chemistry

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Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases ␣-and ␤-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid ␤ peptide (A␤). At present, little is known about the cellular mechanisms that control APP shedding and A␤ generation. Here, we identified a novel protein, transmembrane protein 59 (TMEM59), as a new modulator of APP shedding. TMEM59 was found to be a ubiquitously expressed, Golgi-localized protein. TMEM59 transfection inhibited complex N-and O-glycosylation of APP in cultured cells. Additionally, TMEM59 induced APP retention in the Golgi and inhibited A␤ generation as well as APP cleavage by ␣-and ␤-secretase cleavage, which occur at the plasma membrane and in the endosomes, respectively. Moreover, TMEM59 inhibited the complex N-glycosylation of the prion protein, suggesting a more general modulation of Golgi glycosylation reactions. Importantly, TMEM59 did not affect the secretion of soluble proteins or the ␣-secretase like shedding of tumor necrosis factor ␣, demonstrating that TMEM59 did not disturb the general Golgi function. The phenotype of TMEM59 transfection on APP glycosylation and shedding was similar to the one observed in cells lacking conserved oligomeric Golgi (COG) proteins COG1 and COG2. Both proteins are required for normal localization and activity of Golgi glycosylation enzymes. In summary, this study shows that TMEM59 expression modulates complex N-and O-glycosylation and suggests that TMEM59 affects APP shedding by reducing access of APP to the cellular compartments, where it is normally cleaved by ␣-and ␤-secretase. Processing of the amyloid precursor protein (APP)3 by two different proteases, called ␣-and ␤-secretase, is a central regulatory event in the generation of the amyloid ␤ peptide (A␤), which has a key role in Alzheimer disease (AD) pathogenesis (1). Both ␣-and ␤-secretase cleave the type I membrane protein APP within its ectodomain close to its transmembrane domain (2). This leads to the secretion of soluble forms of APP (APPs) and is referred to as APP shedding. The ␤-secretase is the aspartyl protease BACE1 and cleaves APP at the N terminus of the A␤ peptide domain, thus catalyzing the first step in A␤ peptide generation (3, 4). After the initial cleavage of APP by BACE1, the remaining C-terminal APP fragment is cleaved by ␥-secretase within its transmembrane domain at the C terminus of the A␤ domain, leading to the secretion of the A␤-peptide (5). In contrast to ␤-secretase, ␣-secretase cleaves within the A␤-sequence of APP, and thereby precludes A␤ peptide generation. Additionally, ␣-but not ␤-secretase cleavage generates a secreted form of APP (APPs␣), which has neurotrophic and neuroprotective properties (6 -8). The ␣-secretase is a member of the ADAM family (A disintegrin and metalloprotease) of proteases (9 -12). At present little is known about how the cell controls access of APP to its secretases and the amount of ␣-and ␤-secretase cleavage (reviewed in Refs. 13 and 14). Recent studies increasingl...

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“…These include: heparan sulphate proteoglycans [45,46], cholesterol [47,48] lipid rafts [36,37,49], reticulon family members [50,51] and PAR-4 [52]. Changed V max in the presence of unchanged K m may reflect the loss of a non-competitive inhibitor of b-secretase activity in AD brain, and increased V max for b-secretase has been observed with BACE1 dimerisation [53].…”

Section: Discussionmentioning

confidence: 99%

Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

2006

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b-Secretase is the rate limiting enzymatic activity in the production of amyloid-b peptide, the primary component of senile plaque pathology in Alzheimer's disease (AD). This study performed the first comparative analysis of b-secretase enzyme kinetics in AD and control brain tissue. Results found V max values for b-secretase to be significantly increased, and K m values unchanged in AD temporal cortex compared to matched control temporal cortex. The increased V max in AD cases, did not correlate with levels of BACE1, and decreased BACE1 and BACE2 levels correlated with the severity of neurofibrillary pathology (I-VI), and synaptic loss in AD. These results indicate that increased V max for b-secretase is a feature of AD pathogenesis and this increase does not correlate directly with levels of BACE1, the principal b-secretase in brain.

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Dimerization of β-Site β-Amyloid Precursor Protein-cleaving Enzyme

Cited by 104 publications

References 67 publications

A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

A Noncompetitive BACE1 Inhibitor TAK-070 Ameliorates Aβ Pathology and Behavioral Deficits in a Mouse Model of Alzheimer's Disease

The Novel Membrane Protein TMEM59 Modulates Complex Glycosylation, Cell Surface Expression, and Secretion of the Amyloid Precursor Protein

Altered β‐secretase enzyme kinetics and levels of both BACE1 and BACE2 in the Alzheimer's disease brain

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