[Molecular Pathogenesis of Sporadic Alzheimer's Disease (AD) and Pharmaceutical Research to Develop a Biomarker for AD Diagnosis].
Alzheimer's disease (AD) is the most common senile dementia. One of the pathological characteristics of AD is the appearance of senile plaques composed of amyloid-β (Aβ) depositions. Aβ is generated by consecutive cleavages of Aβ precursor protein (APP) by β- and γ-secretases. The common pathogenesis for familial AD (FAD) is believed to involve misprocessing of APP by γ-secretase, resulting in increased Aβ42 peptide deposition. However, little is known about γ-secretase function in sporadic AD (SAD), which is the major type of AD. This may be because Aβ42 peptide has highly aggregative properties; therefore it is not easy to estimate the quantitative alteration of net Aβ42 in SAD patients. Alcadein is a family of neural type I membrane proteins. Processing of Alcadein by APP α- and γ-secretases results in secretion of non-aggregative peptide, p3-Alc, into CSF and blood. The C-terminuses of Aβ and p3-Alc are altered by FAD-linked genetic mutations in catalytic components of γ-secretase, in association with an increase in minor Aβ and p3-Alc species. Thus p3-Alcs are expected to behave as useful indicators of γ-secretase dysfunction in SAD brain. Quantitative and qualitative analyses of p3-Alcs raise the possibility that γ-secretase dysfunction may exist even in the absence of genetic mutations. p3-Alc peptides may be a novel biomarker for AD and an indicator of γ-secretase dysfunction for drug development.
Hokkaido University, Faculty of Pharmaceutical Sciences, Laboratory of Neuroscience.
Saori
S
Hata
D000544:Alzheimer Disease / Q000175:diagnosis / Q000209:etiology*; D016229:Amyloid beta-Peptides / Q000032:analysis; D016564:Amyloid beta-Protein Precursor / Q000032:analysis; D015415:Biomarkers / Q000032:analysis*; D002135:Calcium-Binding Proteins / Q000502:physiology; D006801:Humans
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; C503225:CLSTN1 protein, human; D002135:Calcium-Binding Proteins; C100690:amyloid beta-protein p3, human