Acetylcholinesterase inhibitors as starting point towards improved Alzheimer’s disease therapeutics

The knowledge about the pathogenesis and the development of the neurodegeneration associated with Alzheimer's disease (AD) has been organised throughout the years into two theories, namely the cholinergic and the amyloid hypotheses. The loss of cholinergic neurotransmission and the abnormal aggregation and deposition of the amyloid-beta peptide (A beta) in the brain are retained as the central events by the two theories, respectively. These phenomena and their pathological consequences are the main targets of the drug discovery strategies based on each hypothesis. However, the two paradigms share some common aspects as shown by several experimental evidences, such that they might even fit into a unifying scenario of neuropathology and neurodegeneration. In this context, in a perspective of drug discovery, the enzyme acetylcholinesterase (AChE) holds a key position, as it is a main target for cholinomimetic AD drugs being responsible for the breakdown of the neurotransmitter, and it is also involved in the aggregation of A beta and the formation of the neurotoxic fibrils. Following this view, in recent years, a drug design strategy has emerged, directed to finding molecules able to inhibit both of these actions exerted by AChE. In this review, we will briefly introduce the biological basis of this strategy, and then will account for the early results obtained in this field in our and in other laboratories. The main focus will be on potential lead compounds for which some experimental evidence exists supporting the hypothesis of their dual action, as AChE inhibitors and blockers of the AChE-induced A beta aggregation.