M1 muscarinic acetylcholine receptor in Alzheimer’s disease

Abstract

The degeneration of cholinergic neurons and cholinergic hypofunction are pathologies associated with Alzheimer's disease (AD). Muscarinic acetylcholine receptors (mAChRs) mediate acetylcholine-induced neurotransmission and five mAChR subtypes (M1-M5) have been identified. Among them, M1 mAChR is widely expressed in the central nervous system and has been implicated in many physiological and pathological brain functions. In addition, M1 mAChR is postulated to be an important therapeutic target for AD and several other neurodegenerative diseases. In this article, we review recent progress in understanding the functional involvement of M1 mAChR in AD pathology and in developing M1 mAChR agonists for AD treatment.Keywords: agonist; Alzheimer's disease; amyloid; cholinergic hypofunction; M1 muscarinic acetylcholine receptor; tau IntroductionAlzheimer's disease (AD) is a debilitating neurodegenerative disorder afflicting millions of people. It is diagnosed by the progressive loss of cognitive function and behavioral defi cits and is characterized by the presence of neurofibrillary tangles (NFTs), senile plaques, cholinergic neuron loss, and neuronal atrophy at autopsy [1,2] . Senile plaques and NFTs are major pathological hallmarks of AD in the brain. Senile plaques consist of deposits of small peptides called β-amyloid (Aβ). Multiple lines of evidence suggest that the overproduction/ aggregation of neurotoxic Aβ in vulnerable brain regions is the primary cause of AD [3][4][5][6] . NFTs are formed by accumulation of hyperphosphorylated tau protein [7, 8] . Tau is a microtubule-binding protein whose function is to stabilize microtubules and facilitate fast axonal transport. Once highly phosphorylated, tau dissociates from microtubules and is prone to aggregate, forming paired helical fi laments that aggregate into NFTs [9, 10] .The third important hallmark of AD is cholinergic hypofunction. The neurotransmitter acetylcholine abnormalities; and (5) reduction in nAChR levels [11][12][13][14][15][16][17][18][19] .Recent evidence indicates that cholinergic hypofunction is closely linked to Aβ and tau pathologies [20] . As a major receptor group for ACh, mAChRs have also been implicated in the pathophysiology of AD. In the present review, we focus on M1 mAChR, the dominant mAChR subtype involved in learning and memory, and discuss its involvement in AD.Neurosci Bull April 1, 2014, 30(2): 295-307 296Overview of the mAChR Family m A C h R s a r e s e v e n -t r a n s m e m b r a n e G -p r o t e i ncoupled receptors. Upon binding to the endogenous neurotransmitter ACh, mAChRs couple to G proteins to transduct signals [21][22][23] . So far, fi ve mAChR subtypes (M1-M5) have been identifi ed and are divided into two categories based on the manner of signal transduction: M1, M3, and M5 subtypes preferentially interact with the G q/11 family of G proteins, activating phospholipase C and mobilizing intracellular calcium, while M2 and M4 subtypes couple to the G o/i family, inhibiting adenylate cyclases and reducing intracel...

Molecular mechanisms of serotonergic action of the HIV-1 antiretroviral efavirenz

“…The M 1 receptor is the most abundant muscarinic subtype in the brain and is known to play a role in cognition, learning and memory, and vigilance. M 1 knockout mice exhibit cognitive deficits [38, 39], hence blockade of the M 1 receptor by efavirenz may contribute to the cognitive impairment observed in patients taking efavirenz [7, 70]. …”

Current and novel therapeutic molecules and targets in Alzheimer's disease

“…A few attempts have been done previously with muscarinic agonists which improved cognitive functions in patients but could not complete the trials as they were nonspecific and activated other subtypes too. 54 However, nicotinic receptors also respond physiologically to ACh and the a7 and a4b2 subtype expressing neurons are particularly seen damaged in AD patients. 55 Over the years, certain M1 subtype selective agonists such as AF102B, AF150, AF267B, and AF292 of AF series drugs have been tried on patients with AD and the compound AF267B has been found to have excellent pharmacokinetics and can even penetrate the bloodebrain barrier with oral administration whereas AF102B, AF150(S), and AF267B were found to have neurotrophic effects, elevated nonamyloidogenic APP, and decreased Ab.…”

Alzheimer’s Disease: Dawn of a New Era?

“…M1 in particular, plays a pivotal role in cognition and memory and are distributed throughout the cortex and hippocampus. M1 muscarinic receptors are believed to play an important role in the regulation of secretase activities and synthesis of Aβ peptide, and subsequent tau hyperphosphorylation and cognitive dysfunction (117,118). M1 receptor activation activates α-secretase and leads to increased secretion of sAPPa and subsequent inhibition α-secretase which then decreases production of Aβ.…”