Protective effects of irbesartan against neurodegeneration in APP/PS1 mice: Unraveling its triple anti-apoptotic, anti-inflammatory and anti-oxidant action

Alzheimer's disease (AD) involves a complex interplay between amyloid-β plaques, oxidative stress, neuroinflammation and apoptosis, suggesting that multi-target therapies may be more effective than single-target treatments. Angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) have shown protective effects against AD in hypertensive patients. However, those poor blood-brain barrier (BBB) permeability exhibit limited efficacy in neurodegenerative disorders. This study investigated the neuroprotective potential of three ARBs and one ACEI using a combined in vitro and in vivo approach. In N2a and N2a-APPswe cell lines, irbesartan showed the most robust effects, notably increasing p-AKT and HMOX1 levels. Based on these results, irbesartan was selected for the following in vivo studies and administered intranasally (40 mg/kg) to APP/PS1 male mice for 10 weeks. Treated animals showed significant improvements in memory performance, as measured by the novel object recognition test and the Morris water maze. Additionally, irbesartan enhanced dendritic spine density, restored mitochondrial bioenergetics and BBB integrity, and reduced apoptotic markers. These effects were accompanied by a marked reduction in oxidative stress and neuroinflammation. Overall, these results support the potential of intranasal irbesartan as a promising multi-target therapeutic strategy for AD, capable of modulating key pathological features, including synaptic dysfunction, mitochondrial dysfunction, oxidative stress, apoptosis, and neuroinflammation.