Regulators of cholinergic signaling in disorders of the central nervous system

Abstract

Cholinergic signaling is crucial in cognitive processes, and degenerating cholinergic projections are a pathological hallmark in dementia. Use of cholinesterase inhibitors is currently the main treatment option to alleviate symptoms of Alzheimer's disease and has been postulated as a therapeutic strategy in acute brain damage (stroke and traumatic brain injury). However, the benefits of this treatment are still not clear. Importantly, cholinergic receptors are expressed both by neurons and by astrocytes and microglia, and binding of acetylcholine to the α7 nicotinic receptor in glial cells results in anti‐inflammatory response. Similarly, the brain fine‐tunes the peripheral immune response over the cholinergic anti‐inflammatory axis. All of these processes are of importance for the outcome of acute and chronic neurological disease. Here, we summarize the main findings about the role of cholinergic signaling in brain disorders and provide insights into the complexity of molecular regulators of cholinergic responses, such as microRNAs and transfer RNA fragments, both of which may fine‐tune the orchestra of cholinergic mRNAs. The available data suggest that these small noncoding RNA regulators may include promising biomarkers for predicting disease course and assessing treatment responses and might also serve as drug targets to attenuate signaling cascades during overwhelming inflammation and to ameliorate regenerative capacities of neuroinflammation.

Targeting the M1 muscarinic acetylcholine receptor in Alzheimer’s disease

“…The neurotransmitter, ACh is primarily synthesised in the nerve terminal cytoplasm from acetyl coenzyme A and choline, in a reaction catalysed by choline acetyltransferase (ChAT). It is then released into the synapse and binds to the two classes of receptors; the G-protein coupled muscarinic receptors and the ionotropic nicotinic receptors, to transmit signals from one neuron to the other [ 20 ]. ACh in the synapse is broken down into choline and acetate, by acetylcholinesterase (AChE), a powerful hydrolytic enzyme [ 21 ].…”

Preface: Cholinergic mechanisms

“…Finally, Winek et al., (2021) review the involvement of cholinergic regulators in disorders of the central nervous system. Therapeutic strategies targeting cholinergic dysfunction after traumatic brain injury have long been explored (Shin & Dixon, 2015).…”

“…Therapeutic strategies targeting cholinergic dysfunction after traumatic brain injury have long been explored (Shin & Dixon, 2015). In their review, Winek et al., (2021) pay particular attention to the involvement as cholinergic regulators of small non‐coding nucleic acids such as microRNAs and tRNA fragments, which may also serve as biomarkers for disease progression. Altogether, this volume hence covers the impact of cholinergic mechanisms at several different levels.…”

Cholinergic blockade of neuroinflammation: from tissue to RNA regulators

“…Notably, several CholinomiRs have been associated with cholinergic–immune system interactions [ 7 ]. Among other sncRNAs, rediscovered tRFs emerged as interesting new regulators that may function like miRs, in addition to other activities such is interaction with RNA-binding proteins [ 19 , 20 ]. This makes both miRs and tRFs particularly suitable for controlling the rapidly changing physiology of the cholinergic network under quiescent and acute neuroimmune conditions.…”