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 4 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.

Plasma Lipids as Biomarkers for Alzheimer's Disease: A Systematic Review

“…In a healthy brain, the beta-secretase/beta-site amyloid precursor protein cleavage enzyme -1 (BACE-1) and gamma-secretase are present in the lipid rafts of the neuronal plasma membrane and cause cleavage of APP forming beta-amyloid. However, in AD, increased cholesterol lipid rafts induce raft clustering and enhance BACE-1 and APP interaction leading to increased beta-amyloid production [ 5 , 20 , 22 ].…”

“…Dysregulation in the brain lipid environment attributes to disturbed BBB, abnormal APP processing, abnormal cytosis, signaling, increased inflammation, oxidation. Long term, these can result in neuronal death, leading to AD (Figure 2 ) [ 22 ].…”

Acute Systemic Inflammatory Response Alters Transcription Profile of Genes Related to Immune Response and Ca2+ Homeostasis in Hippocampus; Relevance to Neurodegenerative Disorders

“…The genes Saa3 and Ch25h, whose expression was significantly increased in AD brains, were significantly activated during systemic inflammation in hippocampus of mouse. Both genes are involved in lipid metabolism, suggesting that inflammation-related lipid disturbances may contribute to AD pathology and may be a strategic target for potential therapies [91].…”

“…These results are important for understanding hippocampal sensitivity to stress and may indicate novel therapeutic targets for age-and neuro-inflammation-related disorders (Figure 7). target for potential therapies [91].…”

Loss of CDC50A function drives Aβ/p3 production via increased β/α-secretase processing of APP

“…When considering non-Mendelian, late-onset forms of AD, one of the themes to emerge from the large scale genome-wide association studies is that genes involved in lipid homeostasis [9] are responsible for, as non-deterministic genetic risk factors, the more common forms of AD. The classical and most well-validated example is Apolipoprotein E (ApoE) [10], an extracellular lipid transporter whose AD-associated isotype can significantly increase AD risk.…”