Role of glycosphingolipids and therapeutic perspectives on Alzheimer's disease.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder dividing into two forms, early onset familial and late onset sporadic forms. Early onset genetic cases (familial AD (FAD)) constitute about 10% of all AD cases. Heretofore, highly fibrillinogenic and pathological Abeta peptide formation is regarded as the fundamental molecular basis for this disorder. Recent enormous efforts to find out a pathogenesis, however, have revealed that this disorder has a multiplicity of causes such as glycosphingolipids abnormalities, impairment of neurotrophin signaling, protein trafficking, and protein turnover. Most of these aspects were disclosed by the studies on FAD-related presenilin. In this review, we will focus on the current knowledge of many abnormal aspects of cellular lipids, especially glycosphingolipids other than a pathogenic Abeta production caused by the mutant presenilins as a model system. Moreover, we will discuss how these glycosphingolipids abnormalities cause the pathological conditions found in this disorder.
Mutoh
Tatsuro
T
Department of Neurology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. tmutoh@fujita-hu.ac.jp
Hirabayashi
Yoshio
Y
Mihara
Takateru
T
Ueda
Madoka
M
Koga
Hiroshi
H
Ueda
Akihiro
A
Kokura
Takako
T
Yamamoto
Hiroko
H
D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000096:biosynthesis; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005732:Gangliosides / Q000378:metabolism; D006028:Glycosphingolipids / Q000378:metabolism*; D006801:Humans; D021962:Membrane Microdomains / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D053764:Presenilin-1; D015398:Signal Transduction / Q000502:physiology
D016229:Amyloid beta-Peptides; D005732:Gangliosides; D006028:Glycosphingolipids; D008565:Membrane Proteins; D009414:Nerve Growth Factors; C508853:PSEN1 protein, human; D053764:Presenilin-1