Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development

Abstract

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies. Furthermore, remarkable advances in translational molecular imaging have now made it possible to probe cholesterol metabolism in the living human brain with PET, which is an important prerequisite for future clinical trials that target the brain cholesterol machinery in Alzheimer's disease patients-with the ultimate aim being to develop disease-modifying treatments. This work summarizes current concepts of how the biosynthesis, transport and clearance of brain cholesterol are affected in Alzheimer's disease. Further, current strategies to reverse these alterations by pharmacotherapy are critically discussed in the wake of emerging translational research tools that support the assessment of brain cholesterol biology not only in animal models but also in patients with Alzheimer's disease.

Keywords: Alzheimer’s disease; brain cholesterol homeostasis; cholesterol lowering therapy; cytochrome P450 46A1 (CYP46A1); translational molecular imaging.

Figure 1

Simplified model of brain cholesterol biology. In the adult mammalian brain, cholesterol is derived mainly from de novo synthesis in astrocytes. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase constitutes the enzyme responsible for the rate-limiting step of cholesterol biosynthesis. Cholesterol is delivered from astrocytes to neurons via ApoE-mediated transport. Excess neuronal cholesterol is primarily eliminated via CYP46A1—a key enzyme that mediates the reaction of cholesterol to 24S-hydroxycholesterol, which readily crosses the blood–brain barrier and can be eliminated from the CNS. Impaired neuronal cholesterol homeostasis can lead to an enhanced formation of neuronal cholesterol deposits, as observed in isogenic induced pluripotent stem cells derived from patients with Alzheimer's disease. Neuronal cholesterol has been linked to the development of amyloid-β and tau pathology in Alzheimer's disease. LDL = low-density lipoprotein.

Figure 2

Putative mechanisms by which brain cholesterol can contribute to pathophysiology of Alzheimer’s disease. (A) Extraneuronal mechanisms that involve the high-risk ApoE4 variant. (1) ApoE4 has been linked to impaired axonal myelination. Excess cholesterol in oligodendrocytes of ApoE4 carriers and reduces myelin basic protein (MBP) ultimately hampering the ability of oligodendrocytes to carry out axonal myelination; (2) ApoE4 inhibits the cyclophilin A (CypA) pathway in pericytes, which involves activation of nuclear factor kappa B (NF-κB) and matrix metalloprotease 9 (MMP9) and is required for a healthy function of tight junctions in the endothelium; (3) The presence of ApoE4 associates with enhanced microglial activation and release of proinflammatory cytokines. (B) Intraneuronal mechanisms that implicate neuronal cholesterol in Alzheimer’s disease (AD). (4) Cholesterol trafficking from neurons to other cells in the CNS is hampered in ApoE4 carriers due to the reduced capability of this particular isoform to transport brain cholesterol; (5) Neuronal cholesterol can be esterified by the enzyme acetyl-coenzyme A acetyltransferase (ACAT) and is stored in form of lipid droplets; (6) Notably, the amyloid precursor protein (APP) is endowed with a flexible transmembrane cavity that binds cholesterol; (7) triggering amyloidogenic processing and generating amyloid-β (Aβ) monomers; (8) Aβ monomer nucleation and formation of Aβ fibrils is accelerated in the presence of membrane-associated cholesterol. Cholesterol accumulates in specialized membrane substructures known as lipid rafts; (9) Aβ plaque formation requires cholesterol, whereas considerable amounts of cholesterol can be found in Aβ plaques; (10) Aβ pathology boosts the formation of neurofibrillary tangles; (11) The formation of neurofibrillary tangles is further accentuated by the attenuation of proteasomal hyperphosphorylated tau (p-tau) degradation through neuronal cholesterol deposits.

Figure 3

Balance between in situ cholesterol biosynthesis and clearance from the brain. A potential hypothesis to conceptualize the enhanced neuronal cholesterol accumulation in Alzheimer's disease constitutes a disturbed balance between de novo biosynthesis and metabolic clearance of neuronal cholesterol. If this concept is validated in future studies, pharmacological therapy that aims at restoring the balance between production and clearance of neuronal cholesterol holds promise to provide therapeutic benefit in patients with Alzheimer's disease.