Time-dependent effect of oligomeric amyloid-β (1-42)-induced hippocampal neurodegeneration in rat model of Alzheimer's disease

Objective: Alzheimer's disease (AD) is characterized with an abnormal deposition of insoluble amyloid-beta (Aβ) peptide plaques, tangles formation and synaptic dysfunction. These result in impaired functioning of neuronal circuits and alter the behavioral response owing to activation of neurotransmitter receptors. Recently, it has been implicated that Aβ influences N-methyl d-aspartate (NMDA) receptor activation in AD; however, the molecular mechanism underlying remains unclear. Thus, emerged specific aim to study the time-course effect of oligomeric Aβ_(1-42) (oAβ_1-42) on the mRNA expression of genes encoding NMDA and acetylcholine receptors in the rat model of AD.

Methods: Aggregated forms of synthetic Aβ Peptides were injected bilaterally into the intrahippocampal region of rat brain using stereotaxic surgery. Behavioral analysis was performed using eight-arm Radial Arm Maze task at the end of experimental period. Euthanized rat brain hippocampal tissue was used to study the mRNA expression of glutamatergic and cholinergic receptor using semiquantitative reverse transcription-polymerase chain reaction.

Results: oAβ_1-42 decreased the gene expression level of α7-nicotinic acetylcholine receptor and increased the mRNA expression of NMDA receptor 2A, and -2B subunits. In particular, oAβ_1-42 aggregates increased the retention time and altered the behavioral response in rats after 15 days of injection. Further, Amyloid-β_1-42 are highly expressed in 15 days after postinjection in hippocampus of adult rats.

Conclusion: Acute exposure of oAβ_1-42 modulated differential gene expression of glutamatergic and cholinergic receptors in hippocampus of adult rats and is duration dependent reflecting changes in hippocampal circuitry system underlying learning and memory impairments.

Abbreviations: AD: Alzheimer's disease, Aβ: amyloid-β; oAβ_1-42: oligomeric Amyloid-β 1-42 full length peptide; CAM: calmodulin; CNS: central nervous system; CR: Congo red; DG: dentate gyrus; EC: entorhinal cortex; HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol; IBO: ibotenic acid; NMDA: N-methyl d-aspartate; NMDAR: N-methyl d-aspartate receptor; NR2A: N-methyl d-aspartate receptor 2A; NR2B: N-methyl d-aspartate receptor 2B; ACh: acetylcholine; α7-nAChR: α7-nicotinic acetylcholine receptor; PBS: phosphate buffered saline; RAM: Radial Arm Maze; ThT: thioflavin T.

Alzheimer’s disease; NMDA receptor; acetylcholine receptor; amyloid-β; hippocampus; spatial learning and memory.