Cholinergic modulation of amyloid precursor protein processing with emphasis on M1 muscarinic receptor: perspectives and challenges in treatment of Alzheimer's disease

• Published in: Journal of neurochemistry 2012-01, Vol.120 (s1), p.22-33
• Main Author: Fisher, Abraham
• Format: Article
• Language: English
• Subjects: Acetylcholine receptors (muscarinic); Agonists; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's; Alzheimer's disease; Amyloid beta-Protein Precursor - metabolism; Amyloid precursor protein; Animals; Antagonists; cholinergic; Cholinergic Agents - pharmacology; Cholinergic Agents - therapeutic use; Cholinergics; Cholinesterase; Cholinesterase inhibitors; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Cognitive ability; Dementia disorders; Disease Models, Animal; Etiology; Humans; Modulation; muscarinic; Neurodegenerative diseases; Neurons; nicotinic; Precursors; Protein Modification, Translational - drug effects; Protein Modification, Translational - physiology; Proteins; Receptor, Muscarinic M1 - agonists; Receptor, Muscarinic M1 - antagonists & inhibitors; Receptor, Muscarinic M1 - metabolism; Receptors; Tau protein; Treatment Outcome; β-amyloid
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2011.07507.x

J. Neurochem. (2012) 120 (Suppl. 1), 22–33. The prescribed drugs for treatment of cognitive deficits in Alzheimer’s disease (AD) patients are regarded as symptomatic drugs. Effective disease modifying therapies are not yet prescribed in AD patients. Three major hallmarks of AD (e.g. cholinergic hypofunction, Aβ and tau neuropathologies) are closely linked raising the expectation that restoring the cholinergic hypofunction to normal, in particular via selective activation of M1 muscarinic receptors, may alter the onset or progression of AD dementia. This review is focused mainly on modulation of amyloid precursor processing and Aβ levels in the brain via cholinergic treatment strategies based on M1 muscarinic agonists versus other cholinergic treatments (e.g. cholinesterase inhibitors prescribed for treatment of AD, M2 antagonists and nicotinic agonists). Advantages and potential drawbacks of these treatment modalities are reviewed versus the notion that due to an elusive etiology of AD, future disease modifiers should address comprehensively most of these AD hallmarks (e.g. Aβ pathology, tau and tangle pathologies, as well as the cholinergic hypofunction and cognitive impairments). This major requirement may be fulfilled with M1‐selective muscarinic agonists and less with other reviewed cholinergic treatments.