Hesperidin, a flavanoglycone abundantly present in citrus fruits, is reported to 
have antioxidant, anti-inflammatory, and neuroprotective properties. Previous 
reports from our laboratory indicated the neuroprotective effect of hesperidin 
against aluminum chloride (AlCl3)-induced memory loss, acetylcholine esterase 
hyperactivity, oxidative stress, and enhanced expression of amyloid β protein 
biosynthesis-related markers. However, their role on AlCl3-induced inflammation, 
caspase activation, Tau pathology, altered Akt/GSK 3β signaling pathway, and Aβ 
clearance marker has not yet been fully elucidated. Intraperitonial injection of 
AlCl3 (100 mg/kg body weight) for 60 days significantly elevated the expressions 
of insulin-degrading enzyme (IDE), cyclin-dependent kinase 5 (CDK 5), and 
phosphoTau (pTau); inflammatory markers such as glial fibrillary acidic protein 
(GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), NF-kB, 
cyclooxygenase-2 (COX-2), interleukin (IL)-1β, IL-4, IL-6, tumor necrosis 
factor-alpha (TNF-α), inducible nitric oxide synthase (iNOS); and apoptotic 
markers including cytosolic cytochrome c (cyto c), caspase-3, caspase-8, and 
caspase-9, and lowered expressions of mitochondrial cyto c, phospho-Akt (pAkt) 
and phospho-glycogen synthase kinase-3β (pGSK-3β) in the hippocampus and cortex. 
Co-administration of hesperidin to AlCl3 rats for 60 days significantly 
ameliorated the aluminum-induced pathological changes. The behavioral studies 
also supported the above findings. Our results imply that treatment with 
hesperidin might be a potent option for treating the symptoms of cognitive 
impairment in Alzheimer's disease by targeting its most prominent hallmarks.