APP Function and Lipids: A Bidirectional Link

Extracellular neuritic plaques, composed of aggregated amyloid-β (Aβ) 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) ɛ4 alleles, closely links AD to lipids. Further, several lipidclasses and fatty acids have been reported to be changed in the brain of AD-affected individuals. Interestingly, the observed lipidchanges in the brain seem not only to be a consequence of the disease but also modulate Aβ generation. In line with these observations protective lipidsbeing able to decrease Aβ generation and also potential negative lipidsin respect to AD were identified. Mechanistically, Aβ peptides are generated by sequential proteolytic processing of the amyloid precursor protein(APP) by β- and γ-secretase. The α-secretase appears to compete with β-secretase for the initial cleavage of APP, preventing Aβ production. All APP-cleaving secretases as well as APP are transmembrane proteins, further illustrating the impact of lipidson Aβ generation. Beside the pathological impact of Aβ, accumulating evidence suggests that Aβ and the APP intracellular domain (AICD) play an important role in regulating lipidhomeostasis, either by direct effects or by affecting gene expression or protein stability of enzymes involved in the de novo synthesisof different lipidclasses. This review summarizes the current literature addressing the complex bidirectional link between lipidsand AD and APP processing including lipidalterations found in AD post mortem brains, lipidsthat alter APP processing and the physiological functions of Aβ and AICD in the regulation of several lipidmetabolism pathways.