Abstract
The number of people with dementia is increasing rapidly due to the increase in the aging population. Alzheimer’s disease (AD) is a type of neurodegenerative dementia caused by the accumulation of abnormal proteins. Genetic mutations, smoking, and several other factors have been reported as causes of AD, but alterations in glycans have recently been demonstrated to play a role in AD. Amyloid-β (Aβ), a cleaved fragment of APP, is the source of senile plaque, a pathological feature of AD. APP has been reported to undergo N- and O-glycosylation, and several Polypeptide N-acetylgalactosaminyltransferases (ppGalNAc-Ts) have been shown to have catalytic activity for the transfer of GalNAc to APP. Since O-glycosylation in the proximity of a cleavage site in many proteins has been reported to be involved in protein processing, O-glycans may affect the cleavage of APP during the Aβ production process. In this report, we describe new findings on the O-glycosylation of APP and Aβ production.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the brain gradually atrophies, resulting in a decline in cognitive and memory function and changes in personality
O-Glycosylated peptides were subjected to a cleavage assay, which revealed that glycosylation inhibits the a disintegrin and metalloproteinase (ADAM)-mediated cleavage of several substrates, including tumor necrosis factor α (TNF-α), interleukin-6 receptor α (IL-6RA), and TGF-β receptor type-1 (TGFBR-1)
It has been reported that epidermal growth factor (EGF)-domain O-GlcNAc transferase (EOGT) is responsible for O-GlcNAc addition to the extracellular domain of Notch1 [82]; EOGT may be responsible for the O-GlcNAc modification of Amyloid precursor protein (APP)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease in which the brain gradually atrophies, resulting in a decline in cognitive and memory function and changes in personality. We describe the possible involvement of glycosylation in the development of AD. Various human diseases caused by abnormalities in glycosylation have been discovered, and the number of reports of such diseases is increasing every year [1,2,3]. Some diseases involving abnormal glycosylation are congenital and are caused by defects or mutations in glycan-related genes. Glycans have been shown to be involved in other diseases, what induces these glycan changes is sometimes unclear. Several reports have shown that glycans are altered with aging [7,8,9]. These glycan changes with aging may affect the onset or progression of aging-related diseases
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