New insights in lipid metabolism: potential therapeutic targets for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is increasingly recognized as being intertwined with the dysregulation of lipid metabolism. Lipids are a significant class of nutrients vital to all organisms, playing crucial roles in cellular structure, energy storage, and signaling. Alterations in the levels of various lipids in AD brains and dysregulation of lipid pathways and transportation have been implicated in AD pathogenesis. Clinically, evidence for a high-fat diet firmly links disrupted lipid metabolism to the pathogenesis and progression of AD, although contradictory findings warrant further exploration. In view of the significance of various lipids in brain physiology, the discovery of complex and diverse mechanisms that connect lipid metabolism with AD-related pathophysiology will bring new hope for patients with AD, underscoring the importance of lipid metabolism in AD pathophysiology, and promising targets for therapeutic intervention. Specifically, cholesterol, sphingolipids, and fatty acids have been shown to influence amyloid-beta (Aβ) accumulation and tau hyperphosphorylation, which are hallmarks of AD pathology. Recent studies have highlighted the potential therapeutic targets within lipid metabolism, such as enhancing apolipoprotein E lipidation, activating liver X receptors and retinoid X receptors, and modulating peroxisome proliferator-activated receptors. Ongoing clinical trials are investigating the efficacy of these strategies, including the use of ketogenic diets, statin therapy, and novel compounds like NE3107. The implications of these findings suggest that targeting lipid metabolism could offer new avenues for the treatment and management of AD. By concentrating on alterations in lipid metabolism within the central nervous system and their contribution to AD development, this review aims to shed light on novel research directions and treatment approaches for combating AD, offering hope for the development of more effective management strategies.

Keywords: Alzheimer’s disease; diet; lipid; lipid metabolism; therapy strategies.

FIGURE 1

Classification of lipids and its main compounds in central nervous system. Lipids are categorized into three fundamental types: simple, compound, and derived. Within the central nervous system, the prevalent lipid species differ from those in other tissues. The flowchart illustrates common brain lipids, which are instrumental in the metabolic interchange between neurons and glial cells. Simple lipids mainly serve as storage molecules and encompass fats and waxes. Compound lipids, including phospholipids and glycolipids, are essential components of cell membranes and may contain additional functional groups. Derived lipids comprise entities such as fatty acids and sterols.

FIGURE 2

Schematic representation of intercellular cholesterol transportation between astrocytes and neurons. Cholesterol synthesis and regulation primarily take place in the endoplasmic reticulum (ER) of astrocytes. Once synthesized, cholesterol is packaged into lipid droplets and transported predominantly from glial cells to neurons. Its efflux is managed by the formation of ApoE-containing HDL-like particles, facilitated especially by ATP-binding cassette (ABC) transporters such as ABCA1 and ABCG1. Retinoid X receptors (RXRs) and liver X receptors (LXRs), part of the nuclear receptor superfamily, regulate cholesterol levels through feedback mechanisms that control its synthesis and efflux, particularly via ABC transporters. Cholesterol is redistributed to neurons through interactions with low-density lipoprotein receptors (LDLR/LDLR1) or heparan sulfate proteoglycans (HSPG). Additionally, the interaction of lipoprotein particles with amyloid beta (Aβ) peptides suggests a complex interplay between cholesterol metabolism and the pathogenesis of Alzheimer’s disease. ApoE, apolipoprotein E; HDL, high-density lipoprotein; ER, endoplasmic reticulum; RXRs, retinoid X receptors; LXRs, liver X Receptors; LDLR, low-density lipoprotein receptor; LRP1, LDLR-related protein 1; HSPG, heparin sulfate proteoglycan. Created with BioRender.com.

FIGURE 3

Main lipids of cell membranes and their dysregulation in AD. (A) Lipids are the primary constituents of cell membranes in the central nervous system. Under physiological conditions, the cell membrane is principally composed of phospholipids arranged in a bilayer. These phospholipids consist of a hydrophilic head and a hydrophobic tail; the tail may be comprised of saturated or unsaturated fatty acids, varying according to the membrane’s function and location. Additionally, cholesterol and sphingolipids are interspersed throughout the membrane, playing a significant role in the formation of lipid rafts. Glycoproteins and glycolipids are embedded in the membrane’s extracellular surface, contributing to cellular recognition and signaling. (B) Lipid rafts are crucial in the amyloidogenic processing of APP, where the enrichment of cholesterol and sphingolipids facilitates the anchoring of AD-related proteins such as β-site APP cleaving enzyme 1 (BACE1) and γ-secretase. The production of Aβ peptides begins with APP embedded in the cell membrane. This protein is sequentially cleaved by β-secretase and γ-secretase enzymes, releasing Aβ peptides into the extracellular space. Over time, these peptides can aggregate to form amyloid plaques. MAMs, rich in cholesterol and sphingomyelin, structurally mirror lipid rafts and are critical for lipid synthesis and trafficking. The steroidogenic acute regulatory protein (StAR) D1 is essential for mitochondrial cholesterol trafficking and is located at the MAM interface between the ER and mitochondria. ER stress induced by amyloid-β may contribute to the upregulation of StARD1. Accumulation of cholesterol in mitochondria disrupts the physical properties of the membrane and impairs the transport of GSH into mitochondria, undermining the mitochondrial antioxidant defense and leading to subsequent oxidative stress. AD, Alzheimer’s disease; AbPP, amyloid-β precursor protein; APP, amyloid precursor protein; MAMs, mitochondria-associated membranes; ER, endoplasmic reticulum.