An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. The underlying pathologic mechanisms of AD are unclear. Over the decades, the development of single target agent did not lead to any successful treatment for AD. A multitarget agent that could tackle more than one AD phenotype may be helpful as a treatment strategy. Cholinesterases (ChEs) including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are currently the drug targets with approved treatments. Moreover, amyloid beta (Aβ) deposition is a hallmark of AD that receives considerable attention. Herein, 9Q, a previously reported dual target inhibitor dealing with cholinergic dysfunction and amyloid deposition for AD treatment, has undergone thorough investigations.In vitro studies revealed that 9Q exhibited over 80% inhibition of ChE activity at 100 μM and more than 30% inhibition of Aβ aggregation at 1 mM concentration. Moreover 9Q was able to penetrate the blood−brain barrier (BBB) and enhance the cerebral acetylcholine level in triple transgenic AD (3xTg-AD) mice. Following one month treatment with 9Q, the amyloid burden and the cognitive deficits in 3xTg-AD mice were significantly ameliorated. It was observed that 9Q treatment mitigated synapse dysfunction, decreased amyloidogenic APP processing, and reduced the tau pathology in 3xTg-AD mice. Taken together, our results suggested that dual inhibition of cholinesterases and Aβ aggregation could be a promising approach in AD treatment.

Stephapierrines A–H, new tetrahydroprotoberberine and aporphine alkaloids from the tubers of Stephania pierrei Diels and their anti-cholinesterase activities

“…Previously reported hypotheses on the progression of AD pathologies included cholinergic dysfunction, amyloid plaques, neurofibrillary tangles, neuroinflammation, and mitochondrial dysfunction, as well as oxidative stress, which are the major hallmarks of AD. 4 Cholinergic hypothesis is one of the theories for AD pathology. Acetylcholine (ACh) neurotransmitter used by cholinergic neurons is considered to play a critical role in the peripheral and central nervous systems.…”

Pathological mechanisms and therapeutic strategies for Alzheimer’s disease

“…Considering the complexity of AD pathology, multifunctional agents designed with multitarget potential could lead to a breakthrough in AD therapeutic development. Preclinical studies on different pathologies and multitarget treatments (Wang et al, 2019;Ju et al, 2020;Ju and Tam, 2020) may provide a pool of lead compounds for future clinical investigations. There is no royal road to overcome AD, but multifunctional drug is likely to give hope for AD treatment.…”

Novelty-induced behavior and memory enhancing activities of aqueous and ethanol extracts of Solanum incanum Linn. fruits in mice

“…MWM is designed to validate and evaluate the neurocognitive disorders and neurocognitive treatments in the investigation of spatial learning and memory in rodents (D'Hooge and De Deyn, 2001;Ju et al, 2020). It was observed that administration of S. incanum fruits extracts showed a significant decreased escape latency value as compared to the scopolamine treated group and this effect is comparable to that of pramiracetam (Pahuja et al, 2012).…”