Alzheimer's Disease Pharmacotherapy in Relation to Cholinergic System Involvement

Abstract

Alzheimer's disease, a major and increasing global health challenge, is an irreversible, progressive form of dementia, associated with an ongoing decline of brain functioning. The etiology of this disease is not completely understood, and no safe and effective anti-Alzheimer's disease drug to prevent, stop, or reverse its evolution is currently available. Current pharmacotherapy concentrated on drugs that aimed to improve the cerebral acetylcholine levels by facilitating cholinergic neurotransmission through inhibiting cholinesterase. These compounds, recognized as cholinesterase inhibitors, offer a viable target across key sign domains of Alzheimer's disease, but have a modest influence on improving the progression of this condition. In this paper, we sought to highlight the current understanding of the cholinergic system involvement in Alzheimer's disease progression in relation to the recent status of the available cholinesterase inhibitors as effective therapeutics.

Keywords: Alzheimer’s disease, cholinergic system, cholinesterase inhibitors, acetylcholinesterase, butyrylcholinesterase.

Figure 1

Schematic representation of the acetylcholine release course and cholinergic hypothesis of AD. (1) Action potential causing influx of Ca²⁺ and subsequent membrane docking of synaptic vesicles; (2) acetylcholine binds to receptors initiating a graded depolarization in the post synaptic cell; (3) AChE catalyzes the breakdown of acetylcholine and choline molecules are reabsorbed by the presynaptic neuron. ACh, acetylcholine; AChE, acetylcholinesterase; Acetyl-CoA, acetyl coenzyme A.

Figure 2

Schematic diagram of pharmacological approaches of Alzheimer’s disease therapies in relation to the main pathogenic mechanisms including cholinergic neuronal degeneration, the amyloid cascade hypothesis, imperfect insulin signalling, τ protein phosphorylation, calcium theory, neuroinflammation, oxidative stress, or others (dysregulation of iron metabolism, reduced glucose utilization, abnormal cholesterol homeostasis, and mitochondrial dysfunction).

Figure 3

Traditional cholinesterase inhibitors (ChEIs). The molecular structures of compounds approved for treatment of Alzheimer’s disease.

Figure 4

The structures of ChEIs in development: Phenserine, Tolserine, and Eseroline.

Figure 5

The molecular structures of naturally derived ChEIs: Huperzine A and B, Galangin, and Cardanol.

Figure 6

Hybrid ChEIs. The molecular structures of donepezil–tacrine hybrid, tacrine–ferulic acid (T6FA) hybrid, and tacrine and 8-hydroxyquinoline hybrids.

Figure 7

The molecular structures of synthetic analogues: Tacrine analogues, (E)-2(benzo[d]thiazol-2-yl)-3-heteroarylacrylonitriles and ladostigil.