Exploring the Dynamic Changes of Brain Lipids, Lipid Rafts, and Lipid Droplets in Aging and Alzheimer's Disease

Abstract

Aging induces complex changes in the lipid profiles across different areas of the brain. These changes can affect the function of brain cells and may contribute to neurodegenerative diseases such as Alzheimer's disease. Research shows that while the overall lipid profile in the human brain remains quite steady throughout adulthood, specific changes occur with age, especially after the age of 50. These changes include a slow decline in total lipid content and shifts in the composition of fatty acids, particularly in glycerophospholipids and cholesterol levels, which can vary depending on the brain region. Lipid rafts play a crucial role in maintaining membrane integrity and facilitating cellular signaling. In the context of Alzheimer's disease, changes in the composition of lipid rafts have been associated with the development of the disease. For example, alterations in lipid raft composition can lead to increased accumulation of amyloid β (Aβ) peptides, contributing to neurotoxic effects. Lipid droplets store neutral lipids and are key for cellular energy metabolism. As organisms age, the dynamics of lipid droplets in the brain change, with evidence suggesting a decline in metabolic activity over time. This reduced activity may lead to an imbalance in lipid synthesis and mobilization, contributing to neurodegenerative processes. In model organisms like Drosophila, studies have shown that lipid metabolism in the brain can be influenced by diet and insulin signaling pathways, crucial for maintaining metabolic balance. The interplay between lipid metabolism, oxidative stress, and inflammation is critical in the context of aging and Alzheimer's disease. Lipid peroxidation, a consequence of oxidative stress, can lead to the formation of reactive aldehydes that further damage neurons. Inflammatory processes can also disrupt lipid metabolism, contributing to the pathology of AD. Consequently, the accumulation of oxidized lipids can affect lipid raft integrity, influencing signaling pathways involved in neuronal survival and function.

Keywords: Alzheimer’s disease; aging; brain lipids; lipid droplets; lipid rafts.

Figure 2

Several lipid classes undergo morphological and functional alterations in patients suffering from AD. Abbreviations: AA: arachidonic acid; MAG: monoacylglycerol; DAG: diacylglycerol; TAG: triacylglycerols, OA: oleic acid; LA: linoleic acid; PC: phosphatidylcholine; PE: phosphatidylethanolamine; DHA: docosahexaenoic acid.

Figure 3

Different alterations of the various lipid classes in the brain during the early stage and late stages of Alzheimer’s disease [108,110,113,115,124,131,132,133,134,135].

Figure 4

The role of cholesterol from lipid rafts and lipid droplets in AD brain. (A) Cholesterol, a key player in integrating APP within lipid rafts, facilitates its trafficking into these microdomains. Wahrle et al. reported that γ -secretase activity, could be modulated by fluctuations in cholesterol levels at the cell membrane. The activity of γ-secretase is inhibited when cholesterol levels decrease while restoring cholesterol stores renews this protein’s function [39,40,143,144]. This figure is licensed under the Creative Commons Attribution-Share Alike 2.5. (B) Lipid droplet accumulation becomes prominent in AD pathology, emphasizing the intricate link between lipid homeostasis, metabolism, and brain aging. AD’s pivotal glial lipid droplet formation mechanism involves toxic lipids derived from neurons. Their role as illustrated in the figure would be neuroprotective [151,152,153,154,155,156]. Abbreviations: AD: Alzheimer’s disease; ApoE: Apolipoprotein E.

Figure 1

Neuroprotective role of lipid droplets (LDs) in the nervous system in the aging brain. In the aging brain, defective mitochondria in neurons generate ROS, activating the JNK and SREBP transcription factors that stimulate lipid synthesis. These newly synthesized lipids undergo peroxidation in the presence of ROS and are subsequently transported to glia, where they are stored in lipid droplets. This process is facilitated by the apolipoprotein E (ApoE). ApoE is primarily produced by astrocytes in the brain and plays a critical role in maintaining and repairing neurons. One of its essential functions is transporting cholesterol and other lipids to neurons, supporting their growth and function. When ROS levels are elevated, the neuroprotective role of glial LDs becomes evident [46,88]. Abbreviations: ROS: reactive oxygen species; FAs: fatty acids; ApoE: Apolipoprotein E; OXPHOS: oxidative phosphorylation; β-oxid: β-oxidation; JNK: c-Jun N-terminal kinase; SREBP: Sterol regulatory element-binding protein.