Bibliographic
Pioglitazone is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist that remains a potential candidate for AD therapy. This interest was originally sparked by pioglitazone’s ability to cross the blood-brain-barrier (BBB) and subsequent findings of its benefits against multiple features of AD pathology. In Tg mice mice overexpressing mutated APP, pioglitazone reduced glial inflammation, normalized cerebral glucose uptake (CGU), and cerebrovascular function e.g.,(cerebral blood flow –CBF), despite limited or no effect on Aβ processing and deposition. The aim of this study was to investigate the effects of pioglitazone in adult and aged A/T mice on AD hallmarks including impaired neuronally-induced CGU and CBF responses, glial activation, amyloidosis and hippocampus-based learning and memory deficits. Data show that pioglitazone exerts beneficial effects in A/T mice with multiple AD hallmarks. Tnese mice recapitulate the AD-related cognitive deficits, amyloid beta (Aβ) and cerebrovascular pathologies, as well as the altered metabolic and vascular coupling responses to increased neuronal activity. Pioglitazone was found to normalize neurometabolic and neurovascular coupling responses to sensory stimulation, and reduced cortical astroglial and hippocampal microglial activation in both age groups. Pioglitazone had no effect on soluble and insoluble Aβ1-40 and Aβ1-42 levels. However, spatial learning and memory deficits in the Morris water maze were not rescued by pioglitazone, but reversal learning was improved in the adult cohort not withstanding a progressing Aβ pathology. The results further suggest a potential benefit of pioglitazone in managing neuroinflammation, cerebral perfusion and glucose metabolism in AD patients devoid of cerebrovascular pathology.