APP Function and Lipids: A Bidirectional Link

Abstract

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) ε4 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 Aβ generation. In line with these observations, protective lipids being able to decrease Aβ generation and also potential negative lipids in 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 lipids on 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 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 Aβ and AICD in the regulation of several lipid metabolism pathways.

Shedding Light on the Molecular Pathology of Amyloid Plaques in Transgenic Alzheimer’s Disease Mice Using Multimodal MALDI Imaging Mass Spectrometry

“…Most of the lipid classes were shown to be crucial players in AD pathogenesis including amyloid plaque pathology. 8,15 Based on the published studies, one could have in view following main mechanisms for the action of lipids in amyloid pathology and senile plaque formation: Firstly, the interaction of amyloid peptides and/or amyloid oligomers with the cellular membranes effecting the membrane lipid homeostasis and/or effecting the organization and physicochemical properties of the membrane bilayer which alters APP processing. 11,40 Secondly, the functional roles of peptides/proteins such as Aβ and APP Intracellular domain (AICD) in the regulation of lipid metabolism pathways either directly or by effecting the gene expressions encoding for APP, BACE1, the Aβ-degrading protease neriplysin (NEP) as well as several enzymes involved in lipid metabolism.…”

“…11,40 Secondly, the functional roles of peptides/proteins such as Aβ and APP Intracellular domain (AICD) in the regulation of lipid metabolism pathways either directly or by effecting the gene expressions encoding for APP, BACE1, the Aβ-degrading protease neriplysin (NEP) as well as several enzymes involved in lipid metabolism. 15,[41][42][43][44][45] Bidirectionally, lipid-peptide/protein interactions, whereby changes in lipids modulate the function of target proteins such as APP and APP-cleaving secretases. 46,47 Finally, catalyzer and/or interfacial role of lipids in amyloid oligomerization and fibrillization.…”

Omega-3 fatty acids, lipids, and apoE lipidation in Alzheimer's disease: a rationale for multi-nutrient dementia prevention

“…In contrast to -secretase processing of APP, which is proposed to be lipid raft associated, -secretase cleavage of APP seems to take place outside of lipid rafts (128,129). APP processing into A, AICD, and other APP fragments is a key part of the physiological function of APP in lipid sensing and lipid regulation (76,77,130,131), which provides a rationale why APP cleavage is very sensitive to alterations in the membrane lipid composition (78,111,132). Besides a possible direct effect of lipids on APP processing, lipids might be important regulators for lateral movement of proteins within the phospholipid bilayer and might, therefore, be critical for substrate/enzyme interaction and, thus, a correct balance between amyloidogenic and non-amyloidogenic APP processing (133).…”

PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes

“…Alzheimer's disease (AD) is the most common cause of dementia in the elderly (Grimm, Mett, Grimm, & Hartmann, 2017). In AD, as in many other neurodegenerative diseases, normal astrocytic processes are compromised, leading to altered neuronal functions and memory deficits (Acosta, Anderson, & Anderson, 2017).…”