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

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, , a previously reported dual target inhibitor dealing with cholinergic dysfunction and amyloid deposition for AD treatment, has undergone thorough investigations. studies revealed that exhibited over 80% inhibition of ChE activity at 100 μM and more than 30% inhibition of Aβ aggregation at 1 mM concentration. Moreover 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 , the amyloid burden and the cognitive deficits in 3xTg-AD mice were significantly ameliorated. It was observed that 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.