Acetylcholinesterase inhibitors targeting the cholinergic anti-inflammatory pathway: a new therapeutic perspective in aging-related disorders

Neuroinflammation and cholinergic dysfunction, leading to cognitive impairment, are hallmarks of aging and neurodegenerative disorders, including Alzheimer's disease (AD). Acetylcholinesterase inhibitors (AChEI), the symptomatic therapy in AD, attenuate and delay the cognitive deficit by enhancing cholinergic synapses. The a7 nicotinic acetylcholine (ACh) receptor has shown a double-edged sword feature, as it binds with high affinity Abeta, promoting intracellular accumulation and Abeta-induced tau phosphorylation, but also exerts neuroprotection by stimulating anti-apoptotic pathways. Moreover, it mediates peripheral and central anti-inflammatory response, being the effector player of the activation of the cholinergic anti-inflammatory pathway (CAIP), that, by decreasing the release of TNF-a, IL-1b, and IL-6, it may have a role in improving cognition. The finding in preclinical models that, in addition to their major function (choline esterase inhibition) AChEIs have neuroprotective properties mediated via a7nAChR and modulate innate immunity, possibly as a result of the increased availability of acetylcholine activating the CAIP, pave the way for new pharmacological intervention in AD and other neurological disorders that are characterized by neuroinflammation. CHRFAM7A is a human-specific gene acting as a dominant negative inhibitor of a7nAChR function, also suggesting a role in affecting human cognition and memory by altering a7nAChR activities in the central nervous system (CNS). This review will summarize the current knowledge on the cholinergic anti-inflammatory pathway in aging-related disorders, and will argue that the presence of the human-restricted CHRFAM7A gene might play a fundamental role in the regulation of CAIP and in the response to AChEI.