The dyshomeostasis of transition metal ions, accumulation of amyloid-â (Aâ) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aâ species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aâ aggregation in vitro and showed disassembly of Aâ aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aâ25-35 were studied in rats. Compared to sham group, Aâ25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-á and IL-1â). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aâ25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-á and IL-1â release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1â production, but failed to block astrocyte activation and TNF-á production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.
Alzheimer Disease Amyloid beta-Peptides