Perspective on Acetylcholinesterase: A Potential Target for Alzheimer’s Disease Intervention

Abstract

Background: Alzheimer's disease (AD) is an unexplained progressive degenerative brain disease; it accounts for 60-70% of dementia cases worldwide, has an estimated global incidence of 24.3 million, and is associated with deterioration of the central nervous system. Acetylcholinesterase (AChE) is an enzyme that catalyzes the breakdown of acetylcholine to acetate and choline. It is also the potential target of most of the clinically used drugs for the treatment of AD. The degeneration of cholinergic neurons and the loss of neural transmission are the main reasons for the decline of cognitive ability in AD patients. Objective: In recent years, the development of targeted drugs in AD has made significant achievements. The global impact of AD continues to grow, and as a result, the focus of disease-modifying therapies remains elusive. The role of treatment is not limited to pharmacology but involves many factors, such as the psychological, social, and economic aspects of the patient and family. AChE is an important target in AD to consider the use of AChE inhibitors in patients with mild to moderate AD, even though the costs are high and no other direct progress has been made. Although there are many AChE inhibitors, there is no selective potent inhibitor for AChE. There is still a need to address human AChE structure, provide key insights into key protein-ligand interactions, and provide the basis for molecular modeling and structure-based drug design. Conclusion: In this review, we briefly introduce the clinical characteristics of AD, the development of crystal structure, and the latest research on AD. In recent years, the development of different strategies for amyloid-β, BACE1, and type-1 interferon receptor alpha-1 has attracted great attention. There is an urgent need to further characterize available instrumental compounds to explore the use of new selectivity and key protein-ligand interactions in AD. In the past few decades, great progress has been made in the treatment of AD, but AD is still one of the world's problems, and the inability to cure AD, indicates that there is an urgent need for new treatments.

Nipecotic Acid Derivatives as Potent Agents against Neurodegeneration: A Preliminary Study

“…Acetylcholinesterase (AchE) catalyzes acetylcholine cleavage to choline and acetate. Since cholinergic neuron degeneration leads to cognitive impairment, AchE is the pharmacological target of most drugs used clinically against AD [ 33 ]. The inhibitory activity of our compounds was estimated by their inhibition of acetylthiocholine breakdown ( Figure 4 ), mediated by AchE contained in a rat brain homogenate.…”

Pomegranate: A Source of Multifunctional Bioactive Compounds Potentially Beneficial in Alzheimer’s Disease

“…An abnormal activation of AChE leads to a decrease in acetylcholine (ACh) neuronal levels with consequently slowing down of learning and memory processes. Currently, three of the drugs approved for the treatment of AD are AChE inhibitors (donepezil, galantamine, and rivastigmine), one is an uncompetitive antagonist of N -Methyl-D-aspartate receptors (NMDA) (memantine), and the Food and Drugs Administration approved two monoclonal antibodies against Aβ (aducanumab and lecanemab) [ 20 , 21 , 22 , 23 ].…”