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


METHODS
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 advanced glycation end products (RAGE) and low-density lipoprotein receptor-related protein 1 (LRP1), which are involved in Aβ influx and efflux, PPARγ and NF-κB p65 at the BBB, as well as hippocampal Aβ, 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.


RESULTS
Treatment with PPARγ agonists, rosiglitazone (0.8 mg·kg(-1) ) and pioglitazone (9.0 mg·kg(-1) ), for 6 weeks significantly increased Aβ efflux and decreased Aβ influx across the BBB in db/db mice. Concomitantly, they decreased hippocampal Aβ1-40 and Aβ1-42 , 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 PPARγ agonists induced the expression of LRP1 gene by activation of PPARγ and suppressed RAGE gene expression by inactivation of NF-κB signalling at the BBB of db/db mice.


CONCLUSIONS
PPARγ agonists modify abnormal Aβ transport across the BBB and this is accompanied by amelioration of β-amyloidosis and an improvement in hippocampal plasticity in diabetic mice.
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Hao
H
Wang
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Fang
F
Chen
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Kai Long
KL
Zhong
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Su Su
SS
Tang
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Mei
M
Hu
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Yan
Y
Long
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Ming Xing
MX
Miao
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Jian Min
JM
Liao
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Hong Bing
HB
Sun
Department of Pharmacology, China Pharmaceutical University, Nanjing, China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing, China.
Hao
H
Hong
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D047495:PPAR gamma / Q000819:agonists* / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism*; D000077205:Pioglitazone; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
D016229:Amyloid beta-Peptides; D047495:PPAR gamma; D010446:Peptide Fragments; D045162:Thiazolidinediones; C078592:amyloid beta-protein (1-40); D000077154:Rosiglitazone; D000077205:Pioglitazone