Acetylcholinesterase Inhibitors Can Interfere In Amyloid-β Self-Assembly: Potential As Multi-Target Drugs for Alzheimer's Disease

Alzheimer’s disease (AD) is one of the most widespread neurodegenerative diseases. As the disease advances, symptoms include confusion, language skill breakdown and long-term memory loss. Amyloid-β (Aβ) is a small protein produced at low levels by normal brain metabolism. In AD, the amount of Aβ becomes disorderly because of abnormal clearance or overproduction. Some researchers have proposed the amyloid cascade hypothesis to illustrate the pathogenesis of AD. In this hypothesis, aggregated forms of Aβ are considered to induce AD pathogenesis.

Aggregation of Aβ involves a multi-step pathway with several interconnected steps. From monomer, the protein presents a lag phase indicative of nucleation, which is considered the rate limiting step, and then rapidly polymerizes to form small soluble aggregates, including oligomers and protofibrils. These intermediates grow by elongation via monomer addition and direct lateral association to form insoluble fibrils. Insoluble fibrils eventually deposit as plaques in the brains of AD patients.

The cholinergic hypothesis suggests that a dysfunction of acetylcholine-containing neurons in the brain contributes considerably to AD cognitive impairment and progressive memory loss as a result of decreased acetylcholine levels. To date, there are three FDA-approved drugs that improve AD symptoms by reducing the activity of acetylcholinesterase. This tactic raises the level of acetylcholine in the synaptic cleft to maintain stable neurotransmission. If acetylcholinesterase inhibitors could also stop Aβ aggregation, they could function as dual-action drugs.

Here, we introduced several analogs of naphthalimide, a known acetylcholinesterase inhibitor, to investigate the interaction between these compounds and different steps of Aβ self-assembly. In our experiments, we focus on four distinct steps: monomer aggregation, oligomer formation, protofibril elongation, and protofibril association. Several of these novel compounds were capable of slowing Aβ self-assembly. These novel naphthalimide analogs are promising compounds for a multitarget therapeutic strategy to confront AD.