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

ABSTRACT:

Background and purpose

There is emerging evidence suggesting that abnormal transport of amyloid-? (A?) across the blood-brain barrier (BBB) is involved in diabetes-associated cognitive decline. We investigated whether PPAR? agonists restore A? transport across the BBB and hippocampal plasticity in db/db mice.

Experimental approach

Efflux and influx of A? across the BBB were determined by stereotaxic intra-cerebral or i.a. infusion of [(125) I]-A?1-40 respectively. Receptor for advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in A? influx and efflux, PPAR? and NF-?B p65 at the BBB, as well as hippocampal A?, caspase-3, Bax and Bcl-2 were assayed by Western 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? efflux and decreased A? influx across the BBB in db/db mice. Concomitantly, they decreased hippocampal A?1-40 and A?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-?B signalling at the BBB of db/db mice.

Conclusions and implications

PPAR? agonists modify abnormal A? transport across the BBB and this is accompanied by amelioration of ?-amyloidosis and an improvement in hippocampal plasticity in diabetic mice.

SUBMITTER: Wang H

PROVIDER: S-EPMC5341223 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Publications

PPARγ agonists regulate bidirectional transport of amyloid-β across the blood-brain barrier and hippocampus plasticity in db/db mice.

Wang Hao H Chen Fang F Zhong Kai Long KL Tang Su Su SS Hu Mei M Long Yan Y Miao Ming Xing MX Liao Jian Min JM Sun Hong Bing HB Hong Hao H

British journal of pharmacology 20151219 2

<h4>Background and purpose</h4>There is emerging evidence suggesting that abnormal transport of amyloid-β (Aβ) across the blood-brain barrier (BBB) is involved in diabetes-associated cognitive decline. We investigated whether PPARγ agonists restore Aβ transport across the BBB and hippocampal plasticity in db/db mice.<h4>Experimental approach</h4>Efflux and influx of Aβ across the BBB were determined by stereotaxic intra-cerebral or i.a. infusion of [(125) I]-Aβ1-40 respectively. Receptor for adv ...[more]

PMID: 26507867

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