Neuroprotective potential of testosterone against aluminium chloride and d-galactose-induced Alzheimer-like pathology aggravated by overcrowding in mice: Role of Nrf2, HO-1, TNF-α, GSK-3β, PI3K and AKT pathway

Alzheimer's disease (AD) is characterized by cognitive deficits and degenerative changes in the brain, accompanied by neurochemical alterations. Overcrowding refers to a condition of stress caused by a high population density. This stress has both physical and psychological effects. We investigated the potential neuroprotective mechanisms of testosterone focusing on Nrf2 and prosurvival, GSK-3β, PI3K and Akt and neuroinflammation pathways; TNF-α, IL-1β and P38 MAPK against AlCl ₃ /d-gal-induced AD in overcrowded mice. Fifty Swiss Albino male mice were treated as follows: Gp 1: mice were i.p injected with saline for 80 days and served as the normal control group, Gp 2: mice were administered AlCl ₃ /d-gal [AlCl ₃ at a dose of (20 mg/kg) followed by d-galactose at a dose of (120 mg/kg) for 40 days], Gp 3: mice were administered AlCl ₃ /d-gal along with exposure to overcrowding for a further 40 days, Gp 4: mice were given AlCl ₃ /d-gal followed by treatment with a single dose of testosterone (100 mg/kg) on day 41 and Gp 5: mice were administered AlCl ₃ /d-gal followed by treatment with a single dose of testosterone on day 41 coupled with exposure to overcrowding for a further 40 days. AlCl ₃ /d-gal and overcrowded AlCl ₃ /d-gal groups resulted in behavioural, neurochemical, and histopathological changes in mice. Testosterone improved animals’ behaviour and mitigated AlCl ₃ /d-gal-induced and overcrowded AlCl ₃ /d-gal-induced Alzheimer-like disease. Testosterone exerted a neuroprotective effect against AlCl ₃ /d-gal-induced Alzheimer-like pathology in both non-crowded and overcrowded groups via upregulation of Nrf2, HO-1, GSK-3β, PI3K and Akt and marked reduction in TNF-α, IL-1β and P38 MAPK.