Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature

Abstract

Background: Aging is accompanied by increasing vulnerability to pathologies such as atherosclerosis (ATH) and Alzheimer disease (AD). Are these different pathologies, or different presentations with a similar underlying pathoetiology?

Discussion: Both ATH and AD involve inflammation, macrophage infiltration, and occlusion of the vasculature. Allelic variants in common genes including APOE predispose to both diseases. In both there is strong evidence of disease association with viral and bacterial pathogens including herpes simplex and Chlamydophila. Furthermore, ablation of components of the immune system (or of bone marrow-derived macrophages alone) in animal models restricts disease development in both cases, arguing that both are accentuated by inflammatory/immune pathways. We discuss that amyloid β, a distinguishing feature of AD, also plays a key role in ATH. Several drugs, at least in mouse models, are effective in preventing the development of both ATH and AD. Given similar age-dependence, genetic underpinnings, involvement of the vasculature, association with infection, Aβ involvement, the central role of macrophages, and drug overlap, we conclude that the two conditions reflect different manifestations of a common pathoetiology.

Mechanism: Infection and inflammation selectively induce the expression of cholesterol 25-hydroxylase (CH25H). Acutely, the production of 'immunosterol' 25-hydroxycholesterol (25OHC) defends against enveloped viruses. We present evidence that chronic macrophage CH25H upregulation leads to catalyzed esterification of sterols via 25OHC-driven allosteric activation of ACAT (acyl-CoA cholesterol acyltransferase/SOAT), intracellular accumulation of cholesteryl esters and lipid droplets, vascular occlusion, and overt disease.

Summary: We postulate that AD and ATH are both caused by chronic immunologic challenge that induces CH25H expression and protection against particular infectious agents, but at the expense of longer-term pathology.

Figure 1

Age-dependence of Alzheimer disease and atherosclerotic vascular disease. Compiled from multiple sources including [2-5].

Figure 2

Occlusions of brain blood vessels (‘circle of Willis’) in controls and AD. Panel (A) shows cerebral arteries from non-demented elderly individuals, whereas Panel (B) shows arteries from AD patients showing atheromatous plaque deposition. Figure reproduced, with permission, from [15].

Figure 3

Differential contribution of vessel wall thickening (dark-brown coloration) to disease. (A) Atherosclerosis is a chronic inflammatory condition characterized by the accumulation of cholesterol-laden macrophages (foam cells) in arterial walls, partial occlusion and, when the plaques rupture, risk of myocardial infarction and stroke. Partial occlusion compromises oxygen supply to other tissues. (B) In Alzheimer disease neuronal loss is accompanied by thickening of brain vessel walls, recruitment of macrophages, and the formation of amyloid deposits of Aβ in the vicinity of the cerebrovasculature. Macrophages are implicated in shuttling Aβ between amyloid deposits and vessel walls. Mechanisms underlying neuronal loss are not understood, but impaired trans-vessel oxygen and glucose delivery, and reduced removal of toxic metabolites, may predispose to neuronal death; impairment of blood–brain barrier function may also contribute.

Figure 4

Aβ in ATH plaque and in AD and senile cerebral amyloid angiopathy (CAA) macrophages and vessels. (A) ATH. Colocalization of iNOS-expressing macrophages with Aβ and platelets in advanced human atherosclerotic plaque. The panel shows double immunohistochemical stain for Aβ (red) and iNOS-positive macrophages (brown), showing close colocalization (arrows). Panel adapted, with permission, from [76]. (B) Aβ (red) in AD neurons and perivascular macrophages (green, anti-CD68 staining, a macrophage marker). Panel adapted, with permission, from [77](C) Aβ (red) in vessel walls in CAA (green staining: tissue transglutaminase, an extracellular matrix remodeling protein). Panel adapted, with permission, from [78].

Figure 5

Spirochetes in Alzheimer disease brain. (A) Detection in an immature senile plaque using a cocktail of specific antibodies against Borrelia burgdori (dark-brown staining). (B)Borrelia sequences in a mature plaque detected using in situ hybridization using a B. burgdorfi probe. (C) Detection in an amorphous plaque using an antibody to bacterial peptidoglycan. (D) Control brain stained with antibodies against B. Burgdorfi. Arrows in B indicate bodies resembling helical spirochetes. Scale bar, 80 μm for (A, D), 30 μm for (B), and 20 μm for (C). Figure kindly provided by Judith Miklossy, Switzerland.

Figure 6

Virus detection in ATH lesions. (A) Herpes simplex virus sequences in a thoracic artery lesion from a patient undergoing coronary bypass surgery detected by in situ hybridization. Scale bar, 25 μm. Panel adapted, with permission, from [187]. (B) Cytomegalovirus sequences in arterial wall from a patient with severe atherosclerosis detected by in situ hybridization. Original magnification 100×. Panel adapted, with permission, from [188].

Figure 7

25OHC induction by immunostimulation or infection promotes cholesterol esterification and foam cell formation. (A) 25OHC is the only oxysterol induced by interferon (IFN) treatment or infection; panel from [309], with permission. (B) 25OHC stimulates cholesterol esterification in intact cells, from [316], with permission. (C) 25OHC is an allosteric effector of ACAT activity in insect cells expressing human ACAT, from [317] with permission; 7KC, 7-ketocholesterol; 6KCh, 6-ketocholestanol; 7αHC, 7α-hydroxycholesterol. (D) Treatment of bone marrow-derived macrophages with low-dose (ca. 0.1 μM) 25OHC, but not cholesterol itself, induces lipid body formation (BODIPY 493/503 fluorescence); scale bar 10 μm. From [318], with permission.

Figure 8

The foam cell hub (simplified). A model for disease development in ATH; similar processes are argued to operate in AD. Only key pathways are depicted. Challenge by infection or proinflammatory agents leads to induction of IFN signaling (*; both IFN-α and IFN-γ. For the specific pathways involved see [257,309] and references therein), upregulation of macrophage CH25H gene expression, and catalytic conversion of part of the cellular cholesterol pool to 25OHC. Acutely, this molecule exerts anti-pathogen effects via an unknown receptor. On chronic inflammatory exposure, hydroxylated cholesterols accumulate, are removed to insoluble intracellular inclusions by ACAT-mediated esterification (allosterically modulated by oxysterols, a), thereby leading to foam cell formation and overt disease. Oxidation by APP/Aβ may divert or enhance this process. APOE and ABCA1 are shown at the periphery to emphasize their role in export. Other key components from Table 1 (not shown in the figure) include LDLR, a trans-cellular receptor for cholesterol mobilization, and CLU, a protein with diverse functions in complement-mediated cell lysis, apoptosis, and lipid transport. Abbreviations: ABCA1, ATP-binding cassette, sub-family A (ABC1), member 1 (cholesterol efflux protein); ACAT, acyl-CoA cholesterol acyltransferase (also known as SOAT); APOE, apolipoprotein E; APP, amyloid-β (A4) precursor protein (Alzheimer precursor protein); CH25H, cholesterol 25-hydroxylase; CLU, clusterin (apolipoprotein J; complement cytolysis inhibitor); CYP27, cytochrome P450 27A1 (sterol 27-hydroxylase); CYP46, cytochrome P450 46A1 [cholesterol 24(S)-hydroxylase]; CYP7B1, cytochrome P450 7B1 (sterol and steroid 7α hydroxylase); EBI2, Epstein–Barr virus (EBV)-induced G protein-coupled receptor 2, IFN, interferon; LPS, lipopolysaccharide; LDLR, low-density lipoprotein receptor; LXR, liver X receptor; 25OHC, 25-hydroxycholesterol.