Role of Glycosphingolipids and Therapeutic Perspectives on Alzheimers Disease

Tatsuro      Mutoh; Yoshio      Hirabayashi; Takateru      Mihara; Madoka      Ueda; Hiroshi      Koga; Akihiro      Ueda; Takako      Kokura; Hiroko      Yamamoto

Abstract

Alzheimers 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 Aβ 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 Aβ 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.

Keywords: Glycosphingolipids, ganglioside, presenilin, neurotrophin, Trk, lipid rafts, cholesterol, familial Alzheimer's disease