Fiscalin-Based Compounds as Multifunctional Agents Against Alzheimer’s Pathology: Addressing Amyloid Toxicity, Iron Overload, and Cholinergic Deficits

Alzheimer’s disease (AD) is the predominant form of age-related dementia and a major neurodegenerative disorder. Its progression is associated with multiple pathological processes, including amyloid-beta (Aβ) deposition, Tau hyperphosphorylation, iron accumulation, mitochondrial dysfunction, and heightened oxidative stress, among other contributing factors [1]. The decline in acetylcholine (ACh) levels due to cholinergic neuron loss further contributes to the cognitive and memory impairments characteristic of AD [2]. With AD cases projected to more than triple by 2050 due to aging populations, and therapeutic options still limited [3], the search for new treatments that directly target these pathological mechanisms is critical. In this context, fiscalins, a class of valine-derived alkaloids with an indolyl moiety and a tricyclic anthranilic acid core, have shown neuroprotective, anticancer, and antimicrobial activities, highlighting their potential therapeutic relevance in AD [4].

This study investigated the in vitro cytotoxicity, neuroprotective potential, and acetylcholinesterase (AChE) inhibitory activity of six synthetic fiscalin derivatives using SH-SY5Y cells differentiated into a cholinergic phenotype. Cytotoxicity was assessed after 24 h of exposure to the compounds (0–50 μM) using the neutral red uptake and MTT reduction assays to define non-cytotoxic concentrations. Neuroprotection against Aβ (50 μM)- and iron(III) (500 or 1000 μM)-induced cytotoxicity was subsequently evaluated following 24 h of co-incubation with the derivatives (10 and 25 μM). Additionally, AChE inhibition was determined using the Ellman’s method.

None of the tested fiscalin derivatives exhibited cytotoxicity at concentrations up to 25 μM. Notably, three compounds significantly reduced Aβ-induced cell death, while five mitigated iron(III)-mediated cytotoxicity. Additionally, five derivatives significantly inhibited AChE activity. Taken together, these findings indicate that fiscalin-based compounds exert multitarget neuroprotective effects relevant to AD pathology, although further studies are needed to elucidate their underlying mechanisms.