Linking lipids to Alzheimer's disease: cholesterol and beyond

Abstract

Lipid-mediated signalling regulates a plethora of physiological processes, including crucial aspects of brain function. In addition, dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders, such as Alzheimer's disease (AD). Although much attention has been given to the link between cholesterol and AD pathogenesis, growing evidence suggests that other lipids, such as phosphoinositides and phosphatidic acid, have an important role. Regulators of lipid metabolism (for example, statins) are a highly successful class of marketed drugs, and exploration of lipid dysregulation in AD and identification of novel therapeutic agents acting through relevant lipid pathways offers new and effective options for the treatment of this devastating disorder.

Figure 1. Contribution of cholesterol and apolipoprotein E metabolism to biogenesis, degradation and assembly of amyloid β-peptide

Cholesterol in the brain is mainly derived from de novo synthesis from the endoplasmic reticulum. Small amounts of cholesterol can also be delivered to the brain from the periphery, via high density liproproteins (HDL), which can cross the blood-brain-barrier (BBB) unlike larger lipoproteins, such as low density lipoproteins (LDL) and very low density lipoproteins (VLDL). Hydroxymethyl glutaryl-coenzyme A (HMG-CoA) reductase mediates the rate-limiting step in de novo cholesterol biosynthesis. Excess free cholesterol is converted into cholesterol-ester by acyl-coenzyme A:cholesterol acyltransferase (ACAT). Inhibition of HMG-CoA reductase by statins leads to decreased levels of Aβ in animal models and ACAT inhibition has been also shown to reduce Aβ levels by a mechanism that remains as yet poorly defined. ApoE-containing HDL-like particles inhibit the aggregation of Aβ, while free ApoE has been shown to promote Aβ aggregation. LDL receptor-related protein (LRP) serves as a neuronal receptor for astrocyte-produced ApoE-containing lipid particles, thus mediating their internalization into neurons where they are broken down. ApoE-containing HDL-like particles inhibit the aggregation of Aβ, while free ApoE has been shown to promote Aβ aggregation in vitro. ABAC1, a regulator of cholesterol efflux, has been also shown to modulate Aβ levels in neurons. For simplicity, Aβ is drawn as free-floating in the cytoplasm, although it is produced in the lumen of neuronal organelles of the late secretory and endolysosomal systems, from where it can be secreted.

Figure 2. Modulation of proteolytic processing of β-amyloid precursor protein (APP) by lipids

(a) The β-amyloid precursor protein (APP) undergoes amyloidogenic processing mediated either by β- and γ-secretases to yield amyloid β-peptide (Aβ) (purple rectangles). Amyloidogenic processing of APP largely occurs in lipid rafts. Cholesterol and LRP, an ApoE receptor, promote the localization of BACE1 to lipid rafts. GGPP (a short chain isoprenoid) has been shown to promote the association of the γ-secretase complex with lipid rafts. Several lipids (shown in bold text) and lipid metabolizing proteins (italicized bold text) influence APP processing through a variety of mechanisms. (b) APP is also subjected in neurons to a non-amyloidogenic pathway mediated by α-secretase. Localization of APP to non-lipid raft compartments favors processing by α-secretase. Isoprenoids, diaglycerol and phospholipase C (PLC) have been shown to promote the non-amyloidogenic pathway. (c) The relative abundance or absence of the lipids listed on the figure directly influences the activity of BACE1 or γ-secretase. Increased levels of cholesterol or ceramide enhance the activity of BACE1. Cholesterol and sphingolipids are positive modulators of γ-secretase activity while SMase and PLD1 have been identified as negative modulators of γ-secretase activity. PLC-mediated hydrolysis of PtdIns(4,5)P₂ promotes amyloidogenesis by stimulating γ-secretase activity and PtdIns(4,5)P₂ has been shown to directly inhibit γ-secretase activity.

Figure 3. Role of lipids in Aβ-induced alterations in neuronal signaling and synaptic plasticity

Aβ oligomers interact with a number of cell surface molecules, such as gangliosides (e.g., GM1) and Ca²⁺-permeable neurotransmitter receptor-channels [e.g., the NMDA and α7 nicotinic acetylcholine receptors (α7nAchR)], to influence neuronal activity and synaptic function in neurons. Some of these receptor-channels, such as the NMDA receptor, are critical for synaptic plasticity and are involved in learning and memory. A variety of Aβ oligomer species have been shown to potently alter synaptic function, in part by enhancing the activity of phospholipase C (PLC), cytosolic phospholipase A2 (cPLA2) and phospholipase D2 (PLD2). PLC hydrolyzes phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P₂] to diacylglycerol (DAG) and inositol-1,4,5-trisphosphate [Ins(1,4,5)P₃]. cPLA2 hydrolyzes phosphatidylcholine (PC) to arachidonate and lysophosphatidylcholine (LPC). PLD2 hydrolyzes PC to phosphatidic acid (PA) and choline. The crosstalk and functional hierarchy among these phospholipases remain to be determined, although a common denominator for their activation appears to be elevation of intracellular Ca²⁺. Decreased dephosphorylation of PtdIns(4,5)P₂ to phosphatidylinositol-4-phosphate (PtdIns4P) resulting from the heterozygous deletion of phosphoinositide phosphatase synaptojanin 1 (Synj1) confers protection against the synaptotoxic action of Aβ oligomers, indicating that phospholipid metabolism can directly influence the susceptibility of neurons to Aβ. PAP, phosphatidic acid phosphatase; DAGK, diacylglycerol kinase.