Multivariate phase-dependent optimization of bioprocesses boosts performance and quality-Why timing (of exposure) matters.

Alzheimer’s disease (AD) is typically manifested as an insidious memory loss, eventually accompanied or followed by other cognitive deficits such as visuospatial and navigation difficulties, as well as executive dysfunction and language impairment. Many cognitive impairments affect normal activities in daily lives, while the onset of the disease usually comes with several behavioral and psychological symptoms of dementia (BPSD). It is estimated that 131 million people will have AD dementia by 2050 which will cause substantial impact on the world. The need for preventive strategies to postpone the onset, retard the progression and mitigate the symptoms of AD is urgent. According to cholinergic theory AChE is responsible for memory dysfunction and cognitive decline due to depletion of ACh in the synaptic cleft. AChE is crucial to cholinergic hypothesis of AD. In AD, there is a markedly increased activity of AChE which leads to the accelerated hydrolysis of ACh and this impairs cholinergic neurotransmission in brain regions whose cholinergic in nature and are responsible for learning and memory like the hippocampus and cortex. Therefore, pharmacological interference with AChE remains one of the best validated approaches to the treatment of AD, confirmed by clinically used drugs like donepezil (DNP) rivastigmine and galantamine. Latest preclinical studies have corroborated AChE as a prospective target for natural and synthetic compounds, establishing AChE inhibitors not only as agents to restore cholinergic tone but also to attenuate oxidative stress, neuroinflammation, and amyloid-β aggregation. That is, a central goal of AD drug discovery must remain the identification of novel AChE inhibitors with multimodal neuroprotective potential. Accordingly, pharmacological inhibition of AChE remains a validated symptomatic strategy, as evidenced by FDA-approved drugs such as DNP, rivastigmine, and galantamine. However, their long-term clinical utility is limited by adverse effects, including hepatotoxicity.