BACKGROUND AND PURPOSEThere 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.
EXPERIMENTAL APPROACHEfflux and influx of Aβ across the BBB were determined by stereotaxic intra-cerebral or i.a. infusion of [125 I]-Aβ 1-40 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.
KEY RESULTSTreatment with PPARγ agonists, rosiglitazone (0.8 mg·kg À1 ) and pioglitazone (9.0 mg·kg À1 ), for 6 weeks significantly increased Aβ efflux and decreased Aβ influx across the BBB in db/db mice. Concomitantly, they decreased hippocampal Aβ 1-40 and Aβ 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 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 AND IMPLICATIONSPPARγ 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.
AbbreviationsAD, Alzheimer's disease; Aβ, amyloid-β; AGEs, advanced glycation end products; BBB, blood-brain barrier; ID, injected dose; LRP1, low-density lipoprotein receptor related protein 1; MWM, Morris water maze; OCT, optimal cutting temperature; PS, population spike; RAGE, receptor for advanced glycation end products; STZ, streptozotocin; TCA, trichloroacetic acid
IntroductionThere is a mass of evidence suggesting that diabetes impacts cognitive function (Ott et al., 1999;Roberts et al., 2014), and epidemiological studies have also indicated that patients with diabetes are at a higher risk of developing Alzheimer's disease (AD) (Kopf and Frölich, 2009;Maher and Schubert, 2009;Morris et al., 2014). Cognitive deficits have also been reported in studies on rodent models of diabetes such as the db/db mice, which exhibit the characteristics of obesity, insulin resistance, hyperglycaemia and also have increased levels of corticosterone in the circulation due to a mutation that inactivates the leptin receptor (Hummel et al., 1996). These db/db mice have decreased levels of brain-derived neurotrophic factor (BDNF) and increased inflammatory cytokines (IL-1β, IL-6 and TNF-α) in the hippocampus, which cause impairments in hippocampusdependent spatial recognition memory, perforant pa...
