# Ramalin Ameliorates Alzheimer's Disease Pathology by Targeting BACE1, HDAC6, and MAPK Pathways

## TL;DR

Ramalin, a natural antioxidant, reduces Alzheimer's disease pathology by targeting BACE1, HDAC6, and the MAPK pathway, offering potential as a disease-modifying treatment.

## Contribution

Ramalin is identified as a novel therapeutic agent that modulates multiple key pathways in Alzheimer's disease pathology.

## Key findings

- Ramalin reduces BACE1 levels via HDAC6 inhibition, independent of transcription or enzymatic activity.
- Ramalin suppresses neuroinflammation by downregulating iNOS and NLRP3 inflammasome in AD models.
- Ramalin improves cognitive performance and restores synaptic function in AD mouse models.

## Abstract

Aberrant deposition 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 alleviates AD pathology by modulating β‐site APP cleaving enzyme 1 (BACE1), histone deacetylase 6 (HDAC6), and the mitogen‐activated protein kinases (MAPK) pathway. Ramalin reduced BACE1 protein levels, independently of its transcription, translation, or enzymatic activity, an effect mediated by inhibition of HDAC6. Consistently, HDAC6 knockout similarly decreased BACE1 levels, highlighting HDAC6 as a key regulator of BACE1. Ramalin further suppressed neuroinflammatory responses by downregulating inducible nitric oxide synthase (iNOS) and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. In AD mouse models, ramalin treatment significantly attenuated neuroinflammation, Aβ plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed Aβ oligomer‐induced synaptic transmission impairment and restored synaptic vesicle recycling in hippocampal neurons. Transcriptomic analysis identified modulation of the MAPK pathway, with reduced phosphorylation of c‐Jun N‐terminal kinase (JNK) and extracellular signal‐regulated kinase (ERK) implicated in tau pathology. These findings establish ramalin as a disease‐modifying intervention that provides neuroprotection through concurrent regulation of BACE1, HDAC6, and MAPK signaling pathway. Collectively, our findings highlight ramalin as a compelling disease‐modifying candidate with the potential to drive a breakthrough approach targeting AD pathology.

Ramalin alleviates Alzheimer's disease pathology by selectively inhibiting HDAC6, reducing BACE1 levels, and suppressing neuroinflammation through downregulation of the NLRP3 inflammasome and iNOS. It restores synaptic function impaired by Aβ toxicity and improves cognitive performance in AD mouse models, APP/PS1 and 3xTg‐AD. Additionally, ramalin modulates the MAPK signaling pathway, reducing tau phosphorylation by inhibiting JNK and ERK activation.