Sabec Marie H, Savage Quentin R, Wood John L, Maskos Uwe
Institut Pasteur, Université Paris Cité, CNRS UMR 3571, Integrative Neurobiology of Cholinergic Systems, 75015, Paris, France.
Physiology, Pharmacology, and Neuroscience, University of Bristol, Bristol, BS8 1TD, UK.
Mol Psychiatry. 2025 Feb;30(2):556-566. doi: 10.1038/s41380-024-02666-7. Epub 2024 Aug 20.
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-淀粉样寡聚体的积累是阿尔茨海默病的一个标志，在病理早期会导致神经和网络功能障碍。海马体在阿尔茨海默病发病机制的早期就会受到影响，然而，可溶性β-淀粉样蛋白对海马体齿状回（DG）亚区域的影响及其与该区域烟碱型乙酰胆碱受体（nAChRs）的相互作用尚不清楚。我们使用过表达的局部模型表明，β-淀粉样蛋白会在小鼠中诱发早发性神经元活动亢进和海马体依赖性记忆缺陷。此外，我们发现，在健康和病理生理条件下，DG区域都受到强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记忆恢复。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，但降低含β2的nAChR功能与促进病理网络中年轻的成年新生神经元有关，这提示了一种可能的保护机制。因此，我们的数据揭示了β-淀粉样蛋白积累早期阶段DG网络水平的变化，并突出了靶向烟碱神经调节的下游后果。
