期刊
FRONTIERS IN MOLECULAR NEUROSCIENCE
卷 10, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fnmol.2017.00063
关键词
APP processing; AICD; Abeta cholesterol; sphingolipids; PUFA; sulfatides; gangliosides
资金
- EU [211696]
- Fundacio la Marato de TV3
- JPND [MindAD 1ED1508]
Extracellular neuritic plaques, composed of aggregated amyloid-beta (A beta) peptides, are one of the major histopathological hallmarks of Alzheimer's disease (AD), a progressive, irreversible neurodegenerative disorder and the most common cause of dementia in the elderly. One of the most prominent risk factor for sporadic AD, carrying one or two aberrant copies of the apolipoprotein E (ApoE) (epsilon)4 alleles, closely links AD to lipids. Further, several lipid classes and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipid changes in the brain seem not only to be a consequence of the disease but also modulate A beta generation. In line with these observations, protective lipids being able to decrease A beta generation and also potential negative lipids in respect to AD were identified. Mechanistically, A beta peptides are generated by sequential proteolytic processing of the amyloid precursor protein (APP) by beta- and gamma-secretase. The alpha-secretase appears to compete with beta-secretase for the initial cleavage of APP, preventing A beta production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipids on A beta generation. Beside the pathological impact of A beta, accumulating evidence suggests that A beta and the APP intracellular domain (AICD) play an important role in regulating lipid homeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesis of different lipid classes. This review summarizes the current literature addressing the complex bidirectional link between lipids and AD and APP processing including lipid alterations found in AD post mortem brains, lipids that alter APP processing and the physiological functions of A beta and AICD in the regulation of several lipid metabolism pathways.
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