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Aberrant deposition of ¦Â©\amyloid (A¦Â) 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 ¦Â©\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, A¦Â plaque burden, and tau hyperphosphorylation, while improving cognitive performance. Notably, ramalin reversed A¦Â 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 A¦Â 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.

Alzheimer¡¯s disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer¡¯s disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-025-01859-8.

SummaryPoly(ADP-ribose) polymerase 1 (PARP1) inhibition improved the ventricular function in Chagas disease (CD). Here, we uncovered that Parp1 depletion enhances cardiac health by regulating CD8+T cell response against Trypanosoma cruzi (Tc) infection. For this, Parp1?/? and wild-type (WT) mice were challenged with Tc and euthanized at acute and chronic phases of parasite replication and CD development, respectively. Parp1?/? mice controlled the chronic parasite persistence and associated inflammatory pathology more effectively than WT mice. Parp1?/? enhanced the maturation and stability of metabolically reprogrammed CD8+ effector and memory T cells with increased cytotoxic effects against the parasite. Mechanistically, PARP1 depletion enhanced the NFATc1 translocation to Pdcd1 promoter in CD8+T cells, altered the PD1:PDL1 stoichiometric ratio between CD8+T and antigen-presenting cells, and promoted CD8+T cell longevity and function during chronic Tc infection. We conclude that molecular and chemical inhibitors of PARP1 would offer a potential therapy to arrest CD pathogenesis. Graphical abstract Highlights?PARP1 inhibits NFATc1 binding to Pdcd1 promoter, impairing CD8+T cells maturity?PARP1 inhibition reprograms metabolic-immune profile of CD8+T cells in Tc infection?PARP1 inhibitors offer a potential therapy to control Tc infection and CD pathology Molecular biology; Immunology; Microbiology; Cell biology