Koukouli_2025_Mol.Psychiatry__

Patient and animal model data suggest a link between the cholinergic neuromodulatory system and the amyloid beta (Abeta) peptide in causing Alzheimer's disease (AD). But how cholinergic dysfunctions contribute to AD pathology remains controversial. In a mouse model of local amyloid pathology, we show that in the early disease stages, the alpha7 nicotinic acetylcholine receptor (nAChR) is an important target of Abeta in the prefrontal cortex (PFC). Using in vivo two-photon calcium imaging and in vivo patch-clamp electrophysiology in the PFC of awake mice, we demonstrate that Abeta-mediated disruption of specifically the alpha7 nAChR subunit, expressed by distinct interneuron subtypes, results in substantial deficits in network activity. This is corroborated by electrophysiology experiments in slices. Combined with computational modeling, we propose that alpha7 nAChRs are occluded by Abeta early in the disease, whereas the heteropentameric alpha5 and beta2 nAChRs are only partially inactivated and potentially provide novel therapeutic targets for intervention. Accordingly, we show that galantamine, an approved acetylcholine-esterase inhibitor (AChE-I), which acts as a positive allosteric modulator (PAM) of alpha5-containing nAChRs at low concentrations, reduces neuronal hyperactivity.