Background: Epigenetic remodeling is emerging as a critical process for both the onset and progression of Alzheimer’s disease (AD), the most common form of neurodegenerative dementia. However, it is not clear to what extent the distribution of histone modifications is involved in AD. Methods: To investigate histone H3 modifications in AD, we compared the genome-wide distributions of H3K4me3 and H3K27me3 in entorhinal cortices from severe sporadic AD patients and from age-matched healthy individuals of both sexes. Results: AD samples were characterized by typical average levels and distributions of the H3K4me3 and H3K27me3 signals. However, AD patients showed a lower H3K4me3 and higher H3K27me3 signal, particularly in males. Interestingly, the genomic sites found differentially trimethylated at the H3K4 between healthy and AD samples involve promoter regions of genes belonging to AD-related pathways such as glutamate receptor signaling. Conclusions: The signatures of H3K4me3 and H3K27me3 identified in AD patients validate the role of epigenetic chromatin remodeling in neurodegenerative disease and shed light on the genomic adaptive mechanisms involved in AD.

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the substantia nigra (SN) and the accumulation of misfolded α-synuclein (aSyn). In addition to neuronal pathology, activated microglia are recognized as key mediators of the neuroinflammatory milieu in PD, contributing to DAergic neuron vulnerability. Emerging evidence suggests that the immune system, particularly T-cell-mediated responses, plays a key role in the pathogenesis of PD. However, the heterogeneity of these immune responses across species and preclinical models with varying regenerative capacities remains poorly understood. A comparative analysis of T-cell infiltration, astroglial reactivity, and DAergic neuronal loss across multiple models and species was performed. These included acute DAergic degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), genetically modified mice with accumulation of aSyn (Thy1-aSyn L61 model), adult zebrafish exposed to MPTP-induced neurotoxicity and human post-mortem midbrain tissue obtained from PD patients. Zebrafish exhibited transient DAergic neurodegeneration, followed by neuronal regeneration and temporary CD4⁺ T-cell infiltration accompanied by an astroglial response and activation of microglia. In contrast, MPTP-treated mice showed a permanent neuronal loss, marked microglial activation, increased astrogliosis and CD8⁺ T-cell infiltration that was negatively correlated with neuronal survival. By contrast, L61 mice exhibited progressive aSyn accumulation with chronic astrogliosis, mild activation of microglia and CD4⁺ T-cell infiltration not directly linked to neuronal loss. Unlike age-matched controls, the SN from PD brains exhibited DAergic degeneration, aSyn aggregation, and elevated CD3⁺ T-cell infiltration, and increased microglial activation. These changes correlated with neuronal loss and aSyn burden. These findings emphasize the species- and model-specific immune profiles underlying PD pathology. Our results reveal that CD4⁺ T-cells contribute to neuronal regeneration following injury in zebrafish. This process is absent in the MPTP and L61 mouse models, which are instead driven by CD8⁺ or CD4⁺, respectively. This work underscores the potential of targeted immunomodulation aimed at T cell–glial interactions to slow neurodegeneration and promote repair in PD.

We previously determined that 2-Methylglutamate (2MeGlu) and 4-aminopentanoic acid (4APA) have neurochemical properties of glutamatergic and GABAergic false neurotransmitters (FNTs); here, we tested whether their activity impacts mouse models with excitation-inhibition (E-I) imbalance. We first screened racemic agents using models caused by E-I imbalance; rac-2MeGlu, but not rac-4APA, suppressed 81% of excitotoxicity in hippocampal slices and increased survival by 105% in Aldh5a1^-/- mice. Enantiomers with the least receptor activity were further tested in more complex models. R-4APA (50 mg/kg) worsened startle behaviors in the Shank3^-/- autism model while S-2MeGlu (50 mg/kg/d over 19 days) improved motor performance by 77% in MPTP-treated mice without changing dopaminergic neurotoxicity; neither agent improved motor function in a human α-synuclein overexpressing mouse. S-2MeGlu (10 mg/kg/d for 8 weeks), but not R-4APA, reversed the spatial working memory deficit in T41 (Thy-1 hAPP^Lond/Swe+ ) mice without significantly changing Aβ plaque density. Single-nucleus transcriptomics following the same chronic exposures in WT mice yielded positively enriched pathways related to protein handling and synaptic regulation in excitatory neurons with S-2MeGlu; R-4APA caused metabolic pathway negative enrichments in multiple cell types. Our data reveal distinct behavioral and transcriptomic impacts of S-2MeGlu and R-4APA and further support S-2MeGlu as a glutamatergic FNT.