Involvement of endoplasmic reticulum stress in amyloid β (1-42)-induced Alzheimer's like neuropathological process in rat brain

Amyloid-beta (A beta) accumulation in the brain is a pathological hallmark of Alzheimer's disease (AD). Endoplasmic reticulum (ER) stress has been implicated in aetiology of neurodegenerative disorders. We studied the involvement of ER stress in A beta-induced neuronal degeneration in rat brain to correlate it with cellular and molecular modifications in A beta-induced Alzheimer's like neuropathological process. A beta ((1-42)) (5 mu g) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats. Acetylcholinesterase (AChE) activity and histological alterations were observed in different brain regions. ER stress-associated proteins- glucose regulated protein-78 (GRP78), eukaryotic translation initiation factor-2 alpha (eIF2 alpha) and growth arrest and DNA damage-inducible protein-153 (GADD153), neuronal marker- microtubule associated protein-2 (MAP-2) and microglial protein- ionized calcium binding adaptor molecule-1 (Iba-1) were measured by western blot. Reduced glutathione (GSH), nitrite level and levels of caspase-12 and caspase-3 were also measured. ER stress inhibitor, salubrinal (1 mg/kg, intraperitoneally, ip) was used to assess the specific role of ER stress. A beta ((1-42))-induced increase in AChE activity, GRP78 and GADD protein levels, dephosphorylation of eIF2-alpha and caspase-12 and caspase-3 levels and decrease in GSH and MAP-2 levels were attenuated by salubrinal. Increase in Iba-1 protein and nitrite levels after A beta ((1-42)) administration were partially attenuated by salubrinal. A beta ((1-42))-induced histological alterations were correlated with findings of ER stress. Results of present study implicate ER stress as a potential molecular mechanism in A beta-induced Alzheimer's like neuropathology which could serve as surrogate biomarker for study of AD progression and efficacy of therapeutic interventions for AD management.