Abstract
Background Lipolysis is regulated by PPAR α / γ and its target genes apoE and ABCA1, which not only control the transport of cholesterol but also the proteolytic degradation of A β -peptide (A β ) plaques, which are found to be deposited in increased number in Alzheimer’s disease (AD). Accordingly, it was shown that PPAR γ -activation stimulates A β -degradation, in an ABCA1- and apoE-dependent manner. Thus, it is reasonable to assume that increased lipolysis may be neuroprotective and could in part minimize the risk of developing dementia. Lipolysis is intensified during fasting, causing a rise in FGF21 levels, which also acts as a key mediator for PPAR α / γ . Therefore, we hypothesized that the FGF21-PPAR pathway may contribute to A β -clearance, via apoE and ABCA1. This in turn may enhance glucose metabolism, leading to improvements in cognition. Methods and results In line with this hypothesis, we were able to show in vitro that application of wild type FGF21 or an FGF21 Analogue (LY2405319; LY; Eli Lilly) to neurons as well as in glial cells, significantly increases mRNA expression of apoE and ABCA1. Application of LY to ex vivo brain slices of APPswe/PS1 Δ e9 (APP/PS1) mice, an AD-mouse model, reduces A β -plaques of up to 30% in comparison to control. These mice are also characterized by diminished glucose uptake in cognitive brain areas, as demonstrated by 18-FDG-positron emission tomography (FDG-PET). Interestingly, daily LY-application for 16 weeks augments central glucose metabolism in APP/PS1 mice, as indicated by an increased FDG uptake up to the value of control mice (C57BL6 mice). Conclusion Thus, we propose that FGF21 activates apoE/ABCA1-induced degradation of A β -plaques, leading to enhanced cognitive function, functionally evidenced by an increased glucose metabolism. Further experiments are necessary to evaluate FGF21 as a therapeutic option for treatment of AD. Funded by the German Research Foundation ( KU 3280/1-1 ).
Published Version
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