Involvement of Lipids in Alzheimer's Disease Pathology and Potential Therapies

Abstract

Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE ϵ4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

Keywords: amyloid precursor protein; apolipoproteins; blood-brain barrier; energy metabolism; inflammation; late-onset Alzheimer’s disease; mitochondria; myelination.

FIGURE 1

Factorsthat affect brain lipid metabolism and the importance of lipids in healthy aging and AD. Factors that affect brain lipid metabolism – Demographic factors, genetics, lifestyle, the environment, and trauma can influence lipid metabolism in the brain. Interestingly, these factors that influence lipid metabolism are also recognized risk factors of AD. Abnormalities in lipid metabolism can contribute to dysfunctional brain networks that associate with AD pathology. Importance of lipid metabolism in brain function and AD pathology – In healthy aging, normal transport of lipids through apolipoproteins contribute to the function of the brain. Homeostatic control of the brain lipid environment is responsible for sustaining a normal BBB, providing the right environment for normal APP processing, the right composition for ion channels and receptors, cytosis, vesicle formation, and secretion, signaling, inflammation, oxidation, energy balance, and membrane biosynthesis and remodeling. Dyshomeostasis in lipid delivery into the brain and its metabolism attributes to disturbed BBB, abnormal APP processing, disturbance in cytosis, signaling, energy balance, and enhanced/sustained inflammation and oxidation. Over time, these processes lead to neuronal death that is the hallmark of AD pathology.

FIGURE 2

The importance of Lipids on APP processing – APP is a transmembrane protein that is cleaved by several proteases: α-secretase, β-secretases, and γ-secretases. Non-amyloidogenic processing of APP− In a cell with a membrane containing normal or high amounts of unsaturated fatty acids, especially DHA, preference is given to cleavage by α-secretase In this case, a well-structured membrane holds onto an intact APP as it is cleaved by the α-secretase and subsequently the α-secretase releasing the secreted ectodomain sAPPα, along with a small protein fragment, p3, and APP intracellular C-terminal domain (AICD) peptide in the extracellular space. sAPPα and p3 do not form neurotoxic fibrils and plaques, and so this process is referred to as non-amyloidogenic APP processing. Amyloidogenic processing of APP – In contrast, PUFA enriched structure of healthy neurons, the presence of saturated and oxidized fatty acids results in the disruption of the cell membrane structure, and this favors β-secretase activation. APP is cleaved at its’ N-terminus by β-secretase, releasing a soluble ectodomain sAPPβ into the extracellular space. γ-secretase subsequently cleaves the cell-associated C-terminus releasing and Aβ peptides of varying lengths into the extracellular space. Insoluble Aβ fibrils aggregate as oligomers that ultimately clump to form plaques within the brain. These plaques contribute to oxidative stress, neuroinflammation, and eventually decreased brain function.