PPAR agonists regulate bidirectional transport of amyloid-beta across the blood-brain barrier and hippocampus plasticity in db/db mice

BACKGROUND AND PURPOSE There is emerging evidence suggesting that abnormal transport of amyloid- beta ( A beta) across the blood- brain barrier ( BBB) is involved in diabetes- associated cognitive decline. We investigated whether PPAR gamma agonists restore A beta transport across the BBB and hippocampal plasticity in db/ db mice. EXPERIMENTAL APPROACH Efflux and influx of A beta across the BBB were determined by stereotaxic intra- cerebral or i. a. infusion of [ 125I]- A beta 1- 40 respectively. Receptor for advanced glycation end products ( RAGE) and low- density lipoprotein receptor- related protein 1 ( LRP1), which are involved in A beta influx and efflux, PPAR gamma and NF-kappa B p65 at the BBB, as well as hippocampal A beta, caspase- 3, Bax and Bcl- 2 were assayed byWestern blot, immunohistochemistry and RT- PCR. In vivo, hippocampal LTP was recorded, and Morris water maze and Y- maze tasks were performed. KEY RESULTS Treatment with PPAR. agonists, rosiglitazone ( 0.8 mg kg-1) and pioglitazone ( 9.0 mg kg-1), for 6 weeks significantly increased A beta efflux and decreased A beta influx across the BBB in db/ db mice. Concomitantly, they decreased hippocampal A beta 1- 40 and A beta 1- 42, suppressed neuronal apoptosis, as indicated by decreased caspase- 3 activity and increased ratio of Bcl- 2/ Bax, and increased hippocampal plasticity, characterized by an enhanced in vivo LTP and better performance in behavioural tests. Furthermore, the PPAR. agonists induced the expression of LRP1 gene by activation of PPAR. and suppressed RAGE gene expression by inactivation of NF-kappa B signalling at the BBB of db/ db mice. CONCLUSIONS AND IMPLICATIONS PPAR gamma agonists modify abnormal A beta transport across the BBB and this is accompanied by amelioration of beta- amyloidosis and an improvement in hippocampal plasticity in diabetic mice.