The accumulation of β-amyloid oligomers is a hallmark of Alzheimer’s disease, inducing neural and network dysfunction in the early stages of pathology. The hippocampus is affected early in the pathogenesis of AD, however the impact of soluble β-amyloid on the dentate gyrus (DG) subregion of the hippocampus and its interaction with nicotinic acetylcholine receptors (nAChRs) within this region are not known. Using a localized model of over-expression, we show that β-amyloid induces early-onset neuronal hyperactivity and hippocampal-dependent memory deficits in mice. Further, we find the DG region to be under potent and sub-type specific nicotinic control in both healthy and pathophysiological conditions, with targeted receptor inhibition leading to a mnemonic rescue against localized amyloidosis. We show that while neurogenesis and synaptic functions are not severely affected in our model, reducing β2-containing nAChR function is associated with the promotion of young adult-born neurons within the pathological network, suggesting a possible protective mechanism. Our data thus reveal the DG network level changes which occur in the early-stages of β-amyloid accumulation and highlight the downstream consequences of targeted nicotinic neuromodulation.

β-淀粉样蛋白寡聚体的积累是阿尔茨海默病的一个标志，在病理学的早期阶段会引起神经和网络功能障碍。海马在 AD 发病的早期就受到影响，然而可溶性 β-淀粉样蛋白对海马齿状回 (DG) 亚区域的影响及其与该区域内烟碱乙酰胆碱受体 (nAChR) 的相互作用尚不清楚。使用局部过度表达模型，我们发现β-淀粉样蛋白会诱导小鼠早发性神经元过度活跃和海马依赖性记忆缺陷。此外，我们发现 DG 区域在健康和病理生理条件下均受到有效且亚型特异性的烟碱控制，靶向受体抑制可导致针对局部淀粉样变性的助记拯救。我们表明，虽然在我们的模型中神经发生和突触功能没有受到严重影响，但减少含 β2 的 nAChR 功能与病理网络内年轻成年神经元的促进有关，这表明可能存在保护机制。因此，我们的数据揭示了 β-淀粉样蛋白积累早期阶段发生的 DG 网络水平变化，并强调了靶向烟碱神经调节的下游后果。