Critical Role of Astroglial Apolipoprotein E and Liver X Receptor-α Expression for Microglial Aβ Phagocytosis

Abstract

Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-␤ (A␤) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble A␤ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by A␤ disposal. Despite the profound effect on A␤ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar A␤. Conditioned medium from TO901317-treated ApoE Ϫ/Ϫ or LXR␣ Ϫ/Ϫ astrocytes did not increase phagocytosis of A␤. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and A␤ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXR␣ and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXR␣ activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar A␤ in response to treatment with TO901317.

Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases

“…In these studies the LXR-agonist T0901317 was able to cross the BBB in vivo and reduce Aβ burdens in mouse brain tissue, however spatial learning only showed little improvement [123]. This was correlated with an increased ABCA1 expression in astrocytes [123] and in neuronal cells [122].…”

“…In these studies the LXR-agonist T0901317 was able to cross the BBB in vivo and reduce Aβ burdens in mouse brain tissue, however spatial learning only showed little improvement [123]. This was correlated with an increased ABCA1 expression in astrocytes [123] and in neuronal cells [122]. The key role played by ABCA1 in the pathogenesis of AD was reported earlier by Koldamova and colleagues (2005 [124]) who demonstrated that APP23 mice lacking abca1 exhibit increased amyloid deposition compared to control animals.…”

“…Therefore, activation of LXR signaling pathway controlling the cholesterol metabolism, in preventing Aβ deposition has been investigated as therapeutic approach by means of LXR-agonist treatment in the APP23 mice as a mouse model of AD [122,123]. In these studies the LXR-agonist T0901317 was able to cross the BBB in vivo and reduce Aβ burdens in mouse brain tissue, however spatial learning only showed little improvement [123].…”

Alzheimer’s Disease: Recent Concepts on the Relation of Mitochondrial Disturbances, Excitotoxicity, Neuroinflammation, and Kynurenines

“…Just like microglia, astrocytes express intra-and extracellular Aβ-degrading enzymatic apparatus upon exposure to Aβ [164]. Furthermore, they also internalize and degrade Aβ, with astroglial ApoE playing crucial roles in both astroglia-and microgliamediated Aβ clearance among experimental conditions [165][166][167][168]. Supporting a potential detrimental role of astrocytes upon chronic activation during AD pathogenesis, viral inactivation of astrocytes alleviated the pathology in a transgenic murine model of AD [169].…”

Microglia in Alzheimer’s disease

“…Sporadic AD is strongly associated with apolipoprotein E ε4 (APOE4) expression, whereas APOE2 expression is protective (44). Astrocytes and microglia express APOE under the control of nuclear hormone receptors, and it plays an important role in Aβ phagocytosis by microglia (45), although it may influence AD through multiple mechanisms. The balance between Aβ production and removal seems to determine amyloid burden in AD brain (46), and dysregulated Aβ clearance rather than increased Aβ production has been linked to the etiology of sporadic AD (47).…”