A Decrease in Neural Sialyltransferase Activity in Alzheimer’s Disease

Maguire, Teresa; Breen, Kieran C.

doi:10.1159/000106944

Cited by 36 publications

(36 citation statements)

References 28 publications

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“…Interestingly, changes in the activity of glycan processing enzymes have been observed in AD brains compared with agematched controls, such as reduction in the activity of sialyltransferases and a corresponding change in general protein glycosylation (70,71). Because sialylation increases APP secretion, a reduced sialyltransferase activity may contribute to the reduced levels of the neuroprotective and neurotrophic APPs␣, as it is found in Alzheimer disease (72).…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…The roles of these O-glycans are elusive, although it has been proposed that APP processing by a-secretase, b-secretase and c-secretase occurs after O-glycosylation of APP, and that O-glycosylated APP is preferentially secreted [26,29]. Interestingly, a recent report demonstrated a new type of tyrosine O-glycosylation on short (Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] to Ab [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] but not on full-length (Ab 1-38 to Ab 1-42 ) Ab fragments [27]. In a study using CSF from AD patients and nondemented controls, an increase in the short Ab fragments carrying the tyrosine-linked glycan was observed in AD patients.…”

Section: App and Glycosylationmentioning

confidence: 99%

The role of protein glycosylation in Alzheimer disease

2013

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Glycosylation is one of the most common, and the most complex, forms of post-translational modification of proteins. This review serves to highlight the role of protein glycosylation in Alzheimer disease (AD), a topic that has not been thoroughly investigated, although glycosylation defects have been observed in AD patients. The major pathological hallmarks in AD are neurofibrillary tangles and amyloid plaques. Neurofibrillary tangles are composed of phosphorylated tau, and the plaques are composed of amyloid b-peptide (Ab), which is generated from amyloid precursor protein (APP). Defects in glycosylation of APP, tau and other proteins have been reported in AD. Another interesting observation is that the two proteases required for the generation of amyloid b-peptide (Ab), i.e. c-secretase and b-secretase, also have roles in protein glycosylation. For instance, c-secretase and b-secretase affect the extent of complex N-glycosylation and sialylation of APP, respectively. These processes may be important in AD pathogenesis, as proper intracellular sorting, processing and export of APP are affected by how it is glycosylated. Furthermore, lack of one of the key components of c-secretase, presenilin, leads to defective glycosylation of many additional proteins that are related to AD pathogenesis and/or neuronal function, including nicastrin, reelin, butyrylcholinesterase, cholinesterase, neural cell adhesion molecule, v-ATPase, and tyrosine-related kinase B. Improved understanding of the effects of AD on protein glycosylation, and vice versa, may therefore be important for improving the diagnosis and treatment of AD patients.

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“…In addition, sialyltransferase activity was reduced in the frontal and temporal cortical lobes and serum of Alzheimer's patients. This may be a specific biochemical event associated with the AD-like neurodegeneration, although no change was observed in the hippocampus (45,46). This significant decrease in the serum sialyltransferase activity may prove to be a useful early biochemical marker of neurodegeneration and may provide an indication of the underlying cellular events that occur during the process of nerve cell death in AD (46).…”

Section: Gd3smentioning

confidence: 99%