PPARs (peroxisome-proliferator-activated receptors) are ligand-activated transcriptional factor receptors belonging to the so-called nuclear receptor family. The three isoforms of PPAR (α, β/δ and γ) are involved in regulation of lipid or glucose metabolism. Beyond metabolic effects, PPARα and PPARγ activation also induces anti-inflammatory and antioxidant effects in different organs. These pleiotropic effects explain why PPARα or PPARγ activation has been tested as a neuroprotective agent in cerebral ischaemia. Fibrates and other non-fibrate PPARα activators as well as thiazolidinediones and other non-thiazolidinedione PPARγ agonists have been demonstrated to induce both preventive and acute neuroprotection. This neuroprotective effect involves both cerebral and vascular mechanisms. PPAR activation induces a decrease in neuronal death by prevention of oxidative or inflammatory mechanisms implicated in cerebral injury. PPARα activation induces also a vascular protection as demonstrated by prevention of post-ischaemic endothelial dysfunction. These vascular effects result from a decrease in oxidative stress and prevention of adhesion proteins, such as vascular cell adhesion molecule 1 or intercellular cell-adhesion molecule 1. Moreover, PPAR activation might be able to induce neurorepair and endothelium regeneration. Beyond neuroprotection in cerebral ischaemia, PPARs are also pertinent pharmacological targets to induce neuroprotection in chronic neurodegenerative diseases.

Midlife cognitive decline is now recognized as a factor of poor prognosis for late-life dementia. Although an epidemiological link has been suggested with high fat diet (HFD)-induced metabolic disorders, the effect of a long period of HFD on midlife cerebrovascular and cognitive functions remains unproven. A cohort of 216 young mice was fed with HFD up to middle age (12 months), and kinetically characterized for metabolic status, including weight, blood lipid profile, hepatic fat accumulation, glucose intolerance, and visceral adiposity. Metabolic disorders were evidenced from 3 months of HFD. Visual recognition memory and flexibility were significantly altered and associated to a visceral adiposity whereas spatial reference memory and working memory did not. Concomitantly, a progressive dysfunction of the vascular endothelium-dependent relaxation was detected in both middle cerebral artery and parenchymal arterioles, with consequences on the regulation of cerebral blood flow, but without any modification of the basal brain tissue MRI perfusion signal. Our data collection empowered us to stratify the mice according to their heterogeneous response to diet, and to propose a statistical prediction model for cognitive impairment, combining visceral adiposity and cerebral vasomotion in a diagnostic perspective of early neurological deficits.