Stimulation of <i>α</i>7 Nicotinic Acetylcholine Receptors by PNU282987 Demonstrates Efferocytosis-Like Activation and Neuroprotection in Human Models of Microglia and Cholinergic Neurons under the Pathophysiological Conditions of Alzheimer’s Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) peptide accumulation, leading to neuroinflammation and neurodegeneration. In early AD stages, neurodegeneration of basal forebrain cholinergic neurons occurs. Microglia, which are brain immune cells, contribute to Aβ clearance and neuroinflammation. This study investigated the therapeutic effects of PNU282987, a selective full agonist of α7 nicotinic acetylcholine receptor (nAChR), using human models of microglia (hiMacs) and basal forebrain cholinergic neurons (hiBFChNs), both differentiated from human induced pluripotent stem cells (hiPSCs). Our findings indicated that PNU282987 markedly enhanced Aβ phagocytosis by microglia and extracellular Aβ clearance. Furthermore, PNU282987 injection reduced Aβ accumulation in the brain of a mouse model. Treatment of hiMacs with PNU282987 upregulated the expressions of efferocytosis-related genes, such as ASAP2, OSM, and THBD. Efferocytosis-like activation by PNU282987 in hiMacs was further suggested by an increased release of the anti-inflammatory cytokine interleukin-10 (IL-10), along with suppression of the pro-inflammatory cytokine IL-1β produced from microglia with Aβ treatment. This indicates a transformation from Aβ-induced inflammatory phagocytosis to an efferocytosis-like anti-inflammatory phagocytosis. PNU282987 also exerted direct neuroprotective effects on hiBFChNs against Aβ and tumor necrosis factor-α. Furthermore, PNU282987 changed the extracellular contents released from Aβ-treated hiMacs and attenuated the neurotoxicity. These results suggest that α7 nAChR stimulation by PNU282987 enhances the therapeutic effects against AD by promoting Aβ clearance with anti-neuroinflammatory regulation in the microglia and providing direct protection to neurons, thereby addressing the inflammatory and neurodegenerative aspects of AD.