Ramalin ameliorates Alzheimer's disease pathology by targeting BACE1, HDAC6, and MAPK pathways

The accumulation of β-amyloid (Aβ) and hyperphosphorylated tau, along with neuroinflammation, are key drivers of Alzheimer’s disease (AD) pathology. Here, we identify ramalin, a natural antioxidant, as a promising therapeutic agent that targets multiple pathological mechanisms in AD models. Ramalin reduces BACE1 protein levels, without affecting its transcription, translation, or proteolytic activity. This reduction is mediated through selective inhibition of histone deacetylase 6 (HDAC6), as confirmed by genome-wide drug target screening and HDAC activity assays. Knockdown of HDAC6 resulted in decreases in BACE1 levels, positioning HDAC6 as a mediator of BACE1 regulation. Ramalin exhibits anti-inflammatory effects by downregulating iNOS and the NLRP3 inflammasome. In AD mouse models, ramalin treatment significantly reduced neuroinflammation, Aβ plaque burden, tau hyperphosphorylation and improved cognitive performance. Notably, ramalin reversed Aβ oligomer-induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis revealed ramalin modulates MAPK signaling pathway, reducing phosphorylation of JNK and ERK, which are implicated in tau pathology. These findings position ramalin as a multi-target therapeutic agent, offering neuroprotection through coordinated modulation of BACE1, tau phosphorylation, and inflammatory pathways. Given these promising results, ramalin represents a potential breakthrough for the treatment of AD by targeting key pathogenic processes at multiple levels.