Pro-inflammatory protein S100A9 targeted by a natural molecule to prevent neurodegeneration onset.

Accumulation of the pro-inflammatory protein S100A9 has been implicated in neuroinflammatory cascades in neurodegenerative diseases (NDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD). S100A9 co-aggregates with other proteins such as α-synuclein in PD and Aß in AD, contributing to amyloid plaque formation and neurotoxicity. The amyloidogenic nature of this protein and its role in chronic neuroinflammation suggest that it may play a key role in the pathophysiology of these diseases. Research into molecules targeting S100A9 could be a potential therapeutic strategy to prevent its amyloidogenic self-assembly and to attenuate the neuroinflammatory response in affected brain tissue. This work suggests that bioactive natural molecules, such as those found in the Mediterranean diet, may have the potential to alleviate neuroinflammation associated with the accumulation of proteins such as S100A9 in neurodegenerative diseases. A major component of extra virgin olive oil (EVOO), hydroxytyrosol (HT), with its ability to interact with and modulate S100A9 amyloid self-assembly and expression, offers a compelling approach for the development of novel and effective interventions for the prevention and treatment of ND. The findings highlight the importance of exploring natural compounds, such as HT, as potential therapeutic options for these complex and challenging neurological conditions.

Physiology of Cellular Prion Proteins in Reproduction.

Cellular prion protein (PrPC) encoded at Prnp gene is well-known to form a misfolded isoform, termed scrapie PrP (PrPSC) that cause transmissible degenerative diseases in central nervous system. The physiological role of PrPC has been proposed by many studies, showing that PrPC interacts with various intracellular, membrane, and extracellular molecules including mitochondrial inner membrane as a scaffold. PrPC is expressed in most cell types including reproductive organs. Numerous studies using PrPC knockout rodent models found no obvious phenotypic changes, in particular the clear phenotypes in development and reproduction have not demonstrated in these knockout models. However, various roles of PrPC have been evaluated at the cellular levels. In this review, we summarized the known roles of PrPC in various cell types and tissues with a special emphasis on those involved in reproduction.

ApoE Isoforms Inhibit Amyloid Aggregation of Proinflammatory Protein S100A9.

Increasing evidence suggests that the calcium-binding and proinflammatory protein S100A9 is an important player in neuroinflammation-mediated Alzheimer's disease (AD). The amyloid co-aggregation of S100A9 with amyloid-ß (Aß) is an important hallmark of this pathology. Apolipoprotein E (ApoE) is also known to be one of the important genetic risk factors of AD. ApoE primarily exists in three isoforms, ApoE2 (Cys112/Cys158), ApoE3 (Cys112/Arg158), and ApoE4 (Arg112/Arg158). Even though the difference lies in just two amino acid residues, ApoE isoforms produce differential effects on the neuroinflammation and activation of the microglial state in AD. Here, we aim to understand the effect of the ApoE isoforms on the amyloid aggregation of S100A9. We found that both ApoE3 and ApoE4 suppress the aggregation of S100A9 in a concentration-dependent manner, even at sub-stoichiometric ratios compared to S100A9. These interactions lead to a reduction in the quantity and length of S100A9 fibrils. The inhibitory effect is more pronounced if ApoE isoforms are added in the lipid-free state versus lipidated ApoE. We found that, upon prolonged incubation, S100A9 and ApoE form low molecular weight complexes with stochiometric ratios of 1:1 and 2:1, which remain stable under SDS-gel conditions. These complexes self-assemble also under the native conditions; however, their interactions are transient, as revealed by glutaraldehyde cross-linking experiments and molecular dynamics (MD) simulation. MD simulation demonstrated that the lipid-binding C-terminal domain of ApoE and the second EF-hand calcium-binding motif of S100A9 are involved in these interactions. We found that amyloids of S100A9 are cytotoxic to neuroblastoma cells, and the presence of either ApoE isoforms does not change the level of their cytotoxicity. A significant inhibitory effect produced by both ApoE isoforms on S100A9 amyloid aggregation can modulate the amyloid-neuroinflammatory cascade in AD.