A novel multi-target compound mitigates amyloid plaques, synaptic deficits, and neuroinflammation in Alzheimer’s disease models

Abstract

Alzheimer’s disease (AD) is characterized by progressive cognitive decline, amyloid plaque accumulation, synaptic dysfunction, and neuroinflammation. This study reports the therapeutic potential of (S)-4-amino-5,5-difluoro-N′-methyl-N′-phenylpentanehydrazide hydrochloride (RA-058HM), a novel compound, in ameliorating these pathological features of AD in the 5xFAD mouse model. RA-058HM was administered orally for 8 weeks, and its multi-target effects – including relief from neuroinflammation, normalization of synaptic transmission, reduction of amyloidogenesis (plaque and soluble oligomers, as well as BACE1 levels), and rescue of cognitive function—were evaluated. To our knowledge, RA-058HM is the first compound to demonstrate simultaneous modulation of these key pathways in the 5xFAD model, highlighting its potential as a comprehensive disease-modifying therapy for AD. Behavioural tests revealed marked improvements in spatial and recognition memory in RA-058HM-treated 5xFAD mice, suggesting a reversal of cognitive deficits. At the molecular level, RA-058HM treatment reduced amyloidogenesis, as evidenced by decreased levels of amyloid precursor protein (APP) and β-secretase (BACE1) in the hippocampus, accompanied by reduced plaque formation, as detected by Thioflavin-S staining. Furthermore, synaptic transmission was restored to near-normal levels in RA-058HM-treated neurons, indicating that RA-058HM effectively rescues synaptic deficits without altering synaptic protein levels of PSD95 and synaptophysin. In addition, treatment of RA-058HM downregulated hippocampal levels of the NLRP3 inflammasome, TNF-α, and GFAP, suggesting a decrease in neuroinflammatory signaling and a modulation of glial activity. Restoration of mitochondrial motility in hippocampal neurons further suggests that RA-058HM may improve cellular energy dynamics. Collectively, these findings indicate that RA-058HM has multifaceted effects on AD pathology, targeting amyloid accumulation, synaptic transmission, neuroinflammation, and mitochondrial function. This study highlights RA-058HM as a promising candidate for AD therapy and underscores the potential of multi-targeted approaches in addressing the complex mechanisms underlying AD progression.