Fungal Metabolites as Promising New Drug Leads for the Treatment of Alzheimer's Disease

Abstract Alzheimer's disease (AD), discovered by Alois Alzheimer in the early 1900s, is a complex and progressive neurodegenerative disorder, characterized by episodes of memory loss, singled out as the most common cause of dementia in the elderly Wolk et al. (2017) [1] . From a molecular point of view, the aggregation of amyloid-β peptides into fibrils is central to the pathogenesis Qiang et al. (2017) [2] . Cognitive decline observed in AD patients is also hypothesized to be related to the reduction of acetylcholine levels in the brain. The increase in living expectancy has been promoting a huge scientific effort to elucidate the pathogenesis in order to find diagnostics markers and to discover new therapeutic agents to treat patients with AD. Fungi have been reported as new sources of the drugs already used in therapeutics of AD, such as Huperzine A, an alkaloid originally isolated from a Chinese plant species ( Huperzia serrata ). This compound is a selective acetylcholinesterase (AChE) inhibitor and presents low toxicity. Some fungal species have been described as sources of Huperzine-like compounds, such as a strain of Cladosporium cladosporioides , an endophyte isolated from H. serrata Zhang et al. (2011) [3] . However, the search for new drugs to treat AD has gained new life after discovering the potential of antioxidant metabolites to treat degenerative diseases such as AD. Good candidates for new drugs as AChE inhibitors, such as fungal metabolites of the arisugacin class, have been studied as highly selective inhibitors of AChE Otoguro et al. (1997) [4] , Huang et al. (2013) [5] . In a more recent study on Talaromyces sp., a marine-derived fungus, it was described that AChE can also be inhibited by compounds with oxaphenalenone skeleton Wu et al. (2015) [6] . Much attention has been given to experimental approaches that can promote the overexpression of fungal bioactive metabolites. Tools like epigenetic induction, integration of omics data, and high-throughput screening have been a strong ally in the search for new fungal metabolites as new drugs Takahashi et al. (2013) [7] . In this chapter, recent developments and new approaches in the search for natural products of fungal origin as new drug leads to AD treatment are discussed.