Implications of oligomeric amyloid-beta (oAβ42) signaling through α7β2-nicotinic acetylcholine receptors (nAChR) on basal forebrain cholinergic neuronal intrinsic excitability and cognitive decline.

Neuronal and network-level hyperexcitability are commonly associated with increased levels of amyloid-beta (Aβ) and contribute to cognitive deficits associated with Alzheimer's disease (AD). However, the mechanistic complexity underlying the selective loss of basal forebrain cholinergic neurons (BFCNs), a well-recognized characteristic of AD, remains poorly understood. In this study we tested the hypothesis that the oligomeric form of amyloid-beta (oAβ42), interacting with α7-containing nicotinic acetylcholine receptor (nAChR) subtypes, leads to subnucleus-specific alterations in BFCN excitability and impaired cognition. We used single-channel electrophysiology to show that oAβ42 activates both homomeric α7- and heteromeric α7β2-nAChR subtypes while preferentially enhancing α7β2-nAChR open-dwell times. Organotypic slice cultures were prepared from male and female ChAT-EGFP mice and current-clamp recordings obtained from BFCNs chronically exposed to pathophysiologically-relevant level of oAβ42 showed enhanced neuronal intrinsic excitability and action potential firing rates. These resulted from a reduction in action potential afterhyperpolarization and alterations in the maximal rates of voltage change during spike depolarization and repolarization. These effects were observed in BFCNs from the medial septum diagonal band (MSDB) and horizontal diagonal band (HDB) but not the nucleus basalis (NB). Lastly, aged male and female APP/PS1 transgenic mice, genetically null for the β2 nAChR subunit gene, showed improved spatial reference memory compared to APP/PS1 aged-matched littermates. Combined, these data provide a molecular mechanism supporting a role for α7β2-nAChR in mediating the effects of oAβ42 on excitability of specific populations of cholinergic neurons and provide a framework for understanding the role of α7β2-nAChR in oAβ42-induced cognitive decline.SIGNIFICANCE STATEMENTAberrant neural activity can occur years before amyloid-beta (Aβ) plaque deposition. Recent evidence has shifted focused toward the epileptogenic potential of soluble, oligomeric forms of Aβ1-42 (oAβ42) and its role in Alzheimer's disease (AD)-related cognitive decline. This study provides insight into the underling mechanisms mediating oAβ42-induced hyperexcitation in neurons particularly susceptible to degeneration in AD. Using single-channel and whole-cell patch clamp recordings, we demonstrate that 1) oAβ42 interacts with α7β2-containing nicotinic receptors (nAChR), altering the intrinsic excitability of specific populations of basal forebrain cholinergic neurons (BFCNs) and 2) α7β2-nAChR signaling contributes to spatial reference memory deficits in the APP/PS1 mouse model of AD. Together, these findings reveal a unique role for α7β2-nAChR signaling during early, AD-related pathological events.