The Novel Multi-Target Iron Chelating-Radical Scavenging Compound M30 Possesses Beneficial Effects on Major Hallmarks of Alzheimer's Disease

Abstract

The aim of the present study was to evaluate the therapeutic effect of the novel neuroprotective multi-target nontoxic, lipophilic, brain permeable monoamine oxidase inhibitor and iron chelating-radical scavenging drug, M30, on the neuropathology and deficits of spatial learning and memory in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) Alzheimer's disease (AD) mice. Here, we report that systemic treatment of APP/PS1 Tg mice with M30 for 9 months, significantly attenuated cognitive impairments in a variety of tasks of spatial learning and memory retention, working memory, learning abilities, anxiety levels, and memory for novel food and nesting behavior. Furthermore, we found that M30 reduced cerebral iron accumulation accompanied by a marked decrease in several AD-like phenotypes, including cerebral APP levels, amyloid β (Aβ) levels and plaques, phospho-APP and phospho-tau. Signaling studies revealed that M30 markedly downregulated the levels of phosphorylated cyclin-dependent kinase 5 and increased protein kinase B and glycogen synthase kinase 3β phosphorylation. Accumulation and deposition of brain iron is central to various neuropathological processes in AD, including oxidative stress, amyloid deposition, and tau phosphorylation. Thus, the concept of iron chelation holds considerable promise as a therapeutic strategy for AD pathogenesis. Here, for the first time, we demonstrated that, when systemically administered to APP/PS1 Tg mice, our novel multifunctional iron chelating/radical scavenging compound, M30, effectively reduced Aβ accumulation and tau phosphorylation, and attenuated memory deficits. These findings suggest that M30 is a potential therapeutic agent for the prevention and treatment of AD.