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Alzheimer's disease (AD) is a progressive, neurodegenerative brain disorder characterized by extracellular accumulations of amyloid β (Aβ) peptides, intracellular accumulation of abnormal proteins, and early loss of basal forebrain neurons. Recent studies have indicated that the conformation of Aβ is crucial for neuronal toxicity, with intermediate misfolded forms such as oligomers being more toxic than the final fibrillar forms. Our previous work shows that Aβ blocks the potassium (K(+)) currents IM and IA in septal neurons, increasing firing rates, diminishing rhythmicity and firing coherence. Evidence also suggests that oxidative stress (OS) plays a role in AD pathogenesis. Thus we wished to determine the effect of oligomeric and fibrillar forms of Aβ₁₋₄₂ on septohippocampal damage, oxidative damage, and dysfunction in AD. Oligomeric and fibrillar forms of Aβ₁₋₄₂ were injected into the CA1 region of the hippocampus in live rats. The rats were sacrificed 24 hours and 1 month after Aβ or sham injection to additionally evaluate the temporal effects. The expression levels of the K(+) voltage-gated channel, KQT-like subfamily, member 2 (KCNQ₂) and the OS-related genes superoxide dismutase 1, 8-oxoguanine DNA glycosylase, and monamine oxidase A, were analyzed in the hippocampus, medial, and lateral septum. Our results show that both forms of Aβ exhibit time-dependent differential modulation of OS and K(+) channel genes in the analyzed regions. Importantly, we demonstrate that Aβ injected into the hippocampus triggered changes in gene expression in anatomical regions distant from the injection site. Thus the Aβ effect was transmitted to anatomically separate sites, because of the functional coupling of the brain structures.


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Neurobiology of Aging





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