HemeOxygenase-1: Transducer of Sterol Dys-Regulation in Alzheimer Disease

Abstract

ADAD is a progressive, degenerative, dementing disorder and the sixth leading cause of the death in the US [1]. It is estimated that by the year 2050 the number of patients living with AD in the US may rise to 13-16 million while the worldwide prevalence could reach a staggering 1 in 85 or 75-100 million cases [2][3][4][5]. Pathological hallmarks of AD include extracellular deposits of β-amyloid (plaques), neurites containing hyperphosphorylated tau (neurofibrillary tangles) and loss of neurons in discrete regions of the basal forebrain, hippocampus and association cortices [6][7][8][9][10][11]. A largely overlooked pathological feature of AD, originally described over a century ago by Alois Alzheimer, is the accumulation of "adipose inclusions" or "lipoid granules" suggesting aberrant lipid homeostasis in this degenerative state [12]. Although medications (cholinesterase inhibitors) capable of conferring transient symptomatic relief are available for the management of AD, there is currently no disease-modifying intervention which unequivocally slows arrests or reverses the degenerative process. Brain Sterols/OxysterolsCholesterol (CH), its precursors and oxysterols have been consistently implicated in brain aging and neurodegeneration [2,[13][14][15]. The mechanisms underlying this relationship, however, remain ill-defined. In the CNS, sterols including CH subserves numerous biological functions essential for cell survival and homeostasis [16]. Mammalian CNS development is highly dependent on CH [17]; it is therefore not surprising that altered CH homeostasis occurs in a host of neurological conditions [18,19]. Glial CH can be enzymatically (via CH 7a-, 24-and 25-hydroxylase) or non-enzymatically (via oxidative stress) metabolized to oxysterols. On the one hand, augmented oxysterol concentrations may protect neural tissues by attenuating β-amyloiddeposition and by activation of the liver X receptor (LXR). The latter mediates up-regulation of apolipoprotein E (apoE) which, in turn, promotes glial CH efflux thatfacilitates neuronal membrane repair. However, LXR activation may also inhibit glial 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and de novo CH biosynthesis. The latter establishes a negative servomechanism that limits the extent of oxysterol production and CH efflux by these cells. Moreover, primary neuronal cultures have been shown to be highly sensitive to 25-OH cytotoxicity, with lesser vulnerability to other common oxysterols such as 7-keto, 22-OH and 7β-OH [20]. Oxysterols may also promote cytotoxicity in primary astrocytes and apoptosis in microglial cells.Several critical lines of evidence have implicated sterol (dys) regulation and the formation of oxysterols in the pathogenesis of AD. For example, genetic association studies have linkedpolymorphisms ofAPOE, SORL1, CLU andABCA7 genes, which directly or indirectlyimpact lipid homeostasis, with the development of AD [21,22]. In addition, dyslipidemia has been identified in several distinct populations as an important midlife risk factor for s...