β-Amyloid Regulates The Expression Of Astrocyte ATP Binding Cassette Transporters Involved In Cholesterol Release: Mechanisms And Implications For Alzheimer’s Disease

Objective Abnormal accumulation and deposit ofβ-amyloid(Aβ)has been implicated as the main culprit of Alzheimer’s Disease(AD), with the majority of research focusing on the detrimental effects of Aβ.Studies have rarely addressed the possible beneficial effects of Aβin normal brain function or in different stages of AD pathogenesis. Based on the recent progress in understanding the roles of Aβ, ATP-binding cassette transporters, and cholesterol metabolism in AD. We study the potential role of Aβin regulating ABCA1,ABCG1 and ABCC1, which are pivotal in cholesterol handling and oxidative stress in the brain.Methods Cortex and hippocampus from 5x FAD mice at different ages with their age-matching controls were probed for the expression of ABCA1,ABCG1 and ABCC1, followed by western blot quantification and immunohistochemical studies. Cortical astrocytes were cultured from neonatal C57BL/6 mice and treated with Aβ1-42, And the effects on ABCA1,ABCG1 and ABCC1 expression, cholesterol metabolism, glutamate release and glutathione release were studied, utilizing methods that include q PCR, western blot, pharmacological manipulations, cholesterol measurement and HPLC quantification of glutamate and glutathione levels.Results(1)In WT mouse cortex and hippocampus, there is an age-dependent gradual increase in ABCA1,ABCG1 and ABCC1 expression. In 5x FAD mice, profound increase in their expression occurred around the age of 2 months and peak around 4.5 months of age, followed by an age-dependent decline to levels below age-matched controls.(2) On cultured astrocytes, Aβat various aggregation forms can stimulate the expression of ABCA1,ABCG1 and ABCC1,with monomeric Aβ(m Aβ) being the most effective in a dose and time-dependent manner.(3) Retinoid X receptor(RXR) plays a pivotal role in regulating ABCA1 and ABCG1 expression.(4) ABCG1 protein has a half- life of approximately 5 days, ABCA1 protein has a half- life of approximately 5 hours.(5)Formyl peptide receptors(FPR)are key mediators of Aβeffects on ABCA1 and ABCG1 expression. Inhibition of either FPR1 or FPR2 could block Aβeffects.(6)Peroxisome proliferator-activated receptor(PPAR)subtype PPARα,but not PPARγparticipates in regulating ABCA1 and ABCG1 expression in astrocytes.(7)Aβand bexarotene stimulation increases cholesterol release from cultured astrocytes, which may significantly increase glutamate release from astrocytes.(8)Aβstimulation increases glutathione release from cultured astrocytesConclusion Through activating FPR1 and FPR2 in astrocytes, Aβdose and time dependently increases ABCA1 and ABCG1 expression, in parallel or synergistically with the regulation by PPARαactivity and the commanding RXR activity. Up-regulation of ABCA1 and ABCG1 can increase the export of astrocyte cholesterol, presumably to better compensate the neuronal cholesterol requirement resulted from Aβand APP inhibition of neuronal cholesterol synthesis in the early stage of AD. And Aβincreases ABCC1 expression and the export of astrocyte glutathione. However,this compensatory effect is eventually diminished by factors associated with the later progression of AD.