Neuroprotective Role of THOP1 in Alzheimer's Disease

Neuroprotective Role of THOP1 in Alzheimer's Disease

Pathway Description

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which no efficacious treatments are available. The amyloid hypothesis postulates that amyloid β (Aβ) deposits are the fundamental cause of the disease. The production of Aβ peptide by proteolytic cleavage of the amyloid precursor protein (APP) and mechanisms associated with Aβ clearance represent central determinants of Aβ levels in the brain. The imbalance in Aβ production and clearance is the primary cause of AD pathogenesis.Thimet oligopeptidase (THOP1) is a phosphoprotein that is expressed primarily in the brain, gonads and the pituitary gland. It is a 78 kDa metalloendopeptidase with a distinctive size-selectivity for peptides ranging from 8 to 17 amino acids. It is thiol-sensitive and requires Zn2+, Mn2+ and Co2+ as cofactors. This enzyme acts on a broad range of substrates including APP, dynorphin A1-8, GnRH and angiotensins I and II, and has been implicated in several events including reproduction, cardiovascular homeostasis and nociception. While THOP1 may be primarily involved in the extracellular metabolism of neuropeptides, it also participates intracellularly in the antigen presentation of peptides generated by the proteasome.

Recent studies have shown that THOP1 expression is significantly increased in human AD brain tissue. Its association with AD was further supported by its reported presence in neurofibrillary tangles and senile plaques in autoptic AD tissue. Interestingly, THOP1 has been associated with the processing of APP at a β-secretase site as well as with the indirect degradation of the Aβ peptide through an as yet unidentified serine protease. Correlating these two findings, it is currently hypothesized that increased THOP1 levels constitutes a compensatory response of neurons to Aβ challenge. Thus, increased amyloid 'load' stimulates an increase in THOP1 protein levels resulting in increased degradation of Aβ.

Neuroprotective Role of THOP1 in Alzheimer's Disease Genes list

Explore Genes related to Neuroprotective Role of THOP1 in Alzheimer's Disease