Progressive neurodegenerative pathologies in aged populations are an issue of major concern worldwide. The microtubule-associated protein tau is able to self-aggregate to form abnormal supramolecular structures that include small oligomers up to complex polymers. Tauopathies correspond to a group of diseases that share tau pathology as a common etiological agent. Since microglial cells play a preponderant role in innate immunity and are the main source of proinflammatory factors in the central nervous system (CNS), the alterations in the cross-talks between microglia and neuronal cells are the main focus of studies concerning the origins of tauopathies. According to evidence from a series of studies, these changes generate a feedback mechanism reactivating microglia and provoking constant cellular damage. Thus, the previously summarized mechanisms could explain the onset and progression of different tauopathies and their functional/behavioral effects, opening the window towards an understanding of the molecular basis of anomalous tau interactions. Despite clinical and pathological differences, increasing experimental evidence indicates an overlap between tauopathies and synucleinopathies, considering that neuroinflammatory events are involved and the existence of protein misfolding. Neurofibrillary tangles of pathological tau (NFT) and Lewy bodies appear to coexist in certain brain areas. Thus, the co-occurrence of synucleinopathies with tauopathies is evidenced by several investigations, in which NFT were found in the substantia nigra of patients with Parkinson’s disease, suggesting that the pathologies share some common features at the level of neuroinflammatory events.

Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder without a cure, despite the enormous number of investigations and therapeutic approaches. AD is a consequence of microglial responses to “damage signals”, such as aggregated tau oligomers, which trigger a neuro-inflammatory reaction, promoting the misfolding of cytoskeleton structure. Since AD is the most prevalent cause of dementia in the elderly (>60 years old), new treatments are essential to improve the well-being of affected subjects. The pharmaceutical industry has not developed new drugs with efficacy for controlling AD. In this context, major attention has been given to nutraceuticals and novel bioactive compounds, such as molecules from the Andean Shilajit (AnSh), obtained from the Andes of Chile. Primary cultures of rat hippocampal neurons and mouse neuroblastoma cells were evaluated to examine the functional and neuroprotective role of different AnSh fractions. Our findings show that AnSh fractions increase the number and length of neuronal processes at a differential dose. All fractions were viable in neurons. The AnSh fractions inhibit tau self-aggregation after 10 days of treatment. Finally, we identified two candidate molecules in M3 fractions assayed by UPLC/MS. Our research points to a novel AnSh-derived fraction that is helpful in AD. Intensive work toward elucidation of the molecular mechanisms is being carried out. AnSh is an alternative for AD treatment or as a coadjuvant for an effective treatment.

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r² = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

Background: Previous research reported the association between circulating Omega‐3 polyunsaturated fatty acids (PUFA) in blood and the risk of dementia and Alzheimer’s disease (AD). However, a large intervention study supplementing Omega‐3 reported that this supplementation has only a marginal effect on improvement of cognitive performance after the supplementation. Since PUFA metabolism shared the processing enzymes, we explored whether the relationship between two main families of PUFA, i.e., Omega‐3 and Omega‐6, might associate with cognitive performance. Hence, we observed that the ratio Omega‐6/Omega‐3 in blood is associated with cognitive decline and dementia. To follow up on this finding, we sought to explore whether modulation of immune response and inflammation may underlie these effects.Method: Three independent cohort were used for this study: i) the observational memory‐clinic‐based cohort DELCODE (n = 1036); ii) the primary care‐derived cohort AgeCoDe (n = 1252); iii) the Multidomain Alzheimer Preventive Trial (MAPT study) cohort (n = 1679). Omega‐3 and PUFA levels were quantified specifically in plasma from each cohort. COX regressions and linear mixed models were applied to evaluate PUFA ratio effect on cognitive performance and progression to dementia. Genomic and epigenomic modulators for the observed effects were further explored using the previously published tool (MetaMeth). Results were confirmed using our pipeline for epigenome‐wide association study (EWAS).Result: Omega‐6/Omega‐3 ratio is associated with cognitive performance and risk of progressing to AD in DELCODE and AgeCoDe. In MAPT, the improvement of this ratio is associated with improvement on cognitive performance. Moreover, levels of Omega‐3 in blood modulate methylation of genes coding for key enzymes of PUFA metabolism. Our data showed that the biological effect for some genetic susceptibility signals for AD is mediated by changes in DNA methylation, including immune‐related genes like MS4A and TREM2.Conclusion: Our data suggests that balance between PUFA is relevant on cognitive decline and dementia. In addition, the genetic effect of risk variants located at the AD risk loci containing the MS4A gene cluster and TREM2 are mediated by changes in methylation. To provide a connection between PUFA and neuroinflammation in the context of AD, we are currently exploring the effect of PUFA levels on DNA methylation at MS4A and TREM2 loci.

Immune matching and rejection pose major hurdles in tissue transplantation. Here, we profile HLA-A , HLA-B , and HLA-C alleles in 3,496 Lithuanian donors genotyped at three-field resolution. The five most frequent alleles constitute 74.6% of HLA-A , 43.2% of HLA-B , and 59.2% of HLA-C , with HLA-A*02:01:01, HLA-B*07:02:01, and HLA-C*07:02:01 being the most common. Lithuanian allele frequencies closely resemble those of populations with pre-Neolithic hunter-gatherer ancestry, such as European-American and British groups. We identified 153 double homozygotes and 51 triple homozygotes for HLA-A , HLA-B , and HLA-C . Compatibility modeling showed triple homozygous profiles match 60.5% of Lithuanians (33.3% for double homozygotes), 13.4% of British population, and 7.4% of European-Americans. CRISPR-Cas9 guide RNA design yielded 54 candidates predicted to disrupt HLA-A or HLA-B , while preserving HLA-C , producing edited profiles matching over 98.1% of Lithuanians, 95.8% of European-Americans, and 95.6% of British population. Finally, we established 16 fibroblast lines from double and triple homozygotes, offering a resource for immune-compatibility studies and regenerative medicine applications.