Co-activation of Selective Nicotinic Acetylcholine Receptor Subtypes Is Required for Neuroprotection against Alzheimer's Disease.

Beta-amyloid peptide (Aβ)-induced suppression of hippocampal GABAergic interneuron activity drives hyperexcitability, amyloid pathology, and cognitive impairment in Alzheimer's disease (AD), suggesting that enhancing hippocampal inhibition may be protective. However, hippocampal interneurons are highly diverse and differentially regulate inhibition and cognition, making it challenging to identify the affected subtypes and optimally restore hippocampal inhibition in AD. We have previously found that Aβ selectively binds to two of the three major hippocampal nicotinic acetylcholine receptor (nAChR) subtypes, α7- and α4β2-nAChRs, but not α3β4-nAChRs, and inhibits these two receptors in hippocampal inhibitory interneurons to decrease their activity, leading to hyperexcitation in excitatory neurons. Here, we further reveal that α7- and α4β2-nAChRs predominantly control nicotinic cholinergic signaling and neuronal activity in hippocampal parvalbumin-positive (PV+) and somatostatin-positive (SST+) inhibitory interneurons, respectively. We also find that systemic co-stimulation of α7- and α4β2-nAChRs is required to reverse hippocampal hyperexcitability, dysfunction of fear learning-associated hippocampal oscillatory activity, and hippocampus-dependent memory loss, and to reduce Aβ pathology in AD model mice. This suggests that co-stimulation of PV+ and SST+ cells via activation of α7- and α4β2-nAChRs together is required to enhance hippocampal inhibition optimally, which reverses hippocampal dysfunction, reduces amyloid pathology, and ultimately prevents memory loss in AD.