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Neurodegenerative disorders especially Alzheimer's disease (AD) are significantly threatening the public health. Acetylcholinesterase (AChE) inhibitors are compounds of great interest which can be used as effective agents for the symptomatic treatment of AD. Although plants are considered the largest source for these types of inhibitors, the microbial production of AChE inhibitors represents an efficient, easily manipulated, eco-friendly, cost-effective, and alternative approach. This review highlights the recent advances on the microbial production of AChE inhibitors and summarizes all the previously reported successful studies on isolation, screening, extraction, and detecting methodologies of AChE inhibitors from the microbial fermentation, from the earliest trials to the most promising anti-AD drug, huperzine A (HupA). In addition, improvement strategies for maximizing the industrial production of AChE inhibitors by microbes will be discussed. Finally, the promising applications of nano-material-based drug delivery systems for natural AChE inhibitor (HupA) will also be summarized. Key Points • AChE inhibitors are potential therapies for Alzheimer's disease. • Microorganisms as alternate sources for prospective production of such inhibitors. • Research advances on extraction, detection, and strategies for production improvement. • Nanotechnology-based approaches for an effective drug delivery for Alzheimer's disease.

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Based on the broad clinical utility of the immunosuppressant mycophenolic acid (MPA), this article aims to intensify the biosynthetic potential of Penicillium roqueforti for more effective hyperproduction of the drug. Several mutants were generated from irradiation mutagenesis and screened. Two strains (GM1013 and GM1093) presented an elevated MPA productivity with significant yield constancy over 10 subsequent generations. By investigating the effect of some phosphorous sources and mineral salts on MPA production by the two mutants, KH 2 PO 4 and FeSO 4 ⋅7H 2 O were most preferred by the two mutants for higher MPA production rates. Statistics-dependent experimental designs were also employed for optimizing medium components for maximum MPA production.Medium components were primarily screened using the Plackett-Burman model to demonstrate the most important components that most significantly affect MPA production. The concentrations of these significant components were then optimized through a central composite rotatable model. In conclusion, gammaradiation mutation and response surface optimization resulted in a promising MPA productivity by P. roqueforti GM1013. To our knowledge, the MPA-yield achieved in this study (2933.32 mg L -1 ) is the highest reported by academic laboratories from P. roqueforti cultures, which could be of economic value for a prospective large industrialized application.

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Huperzine A (HupA) is an anti‐Alzheimer’s therapeutic and a dietary supplement for memory boosting that is extracted mainly from Huperziacae plants. Endophytes represent the upcoming refuge to protect the plant resource from distinction but their HupA yield is still far from commercialization. In this context, UV and gamma radiation mutagenesis of the newly isolated HupA‐producing Alternaria brassicae AGF041 would be applied in this study for improving the endophytic HupA yield. Compared to non‐irradiated cultures, UV (30–40 min, exposure) and γ (0·5 KGy, dose) irradiated cultures, each separately, showed a significant higher HupA yield (17·2 and 30·3%, respectively). While, application of a statistically optimized compound irradiation (0·70 KGy of γ treatment and 42·49 min of UV exposure, sequentially) via Response Surface Methodology (RSM) resulted in 53·1% production increase. Moreover, a stable selected mutant strain CM003 underwent batch cultivation using a 6·6 l bioreactor for the first time and was successful for scaling up the HupA production to 261·6 µg l−1. Findings of this research are demonstrated to be valuable as the employed batch fermentation represents a successful starting step towards the promising endophytic HupA production at an industrial scale.

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