Secondary Modification of S100B Influences Anti Amyloid-ß Aggregation Activity and Alzheimer's Disease Pathology.

Proteinaceous aggregates accumulate in neurodegenerative diseases such as Alzheimer's Disease (AD), inducing cellular defense mechanisms and altering the redox status. S100 pro-inflammatory cytokines, particularly S100B, are activated during AD, but recent findings reveal an unconventional molecular chaperone role for S100B in hindering Aß aggregation and toxicity. This suggests a potential protective role for S100B at the onset of Aß proteotoxicity, occurring in a complex biochemical environment prone to oxidative damage. Herein, we report an investigation in which extracellular oxidative conditions are mimicked to test if the susceptibility of S100B to oxidation influences its protective activities. Resorting to mild oxidation of S100B, we observed methionine oxidation as inferred from mass spectrometry, but no cysteine-mediated crosslinking. Structural analysis showed that the folding, structure, and stability of oxidized S100B were not affected, and nor was its quaternary structure. However, studies on Aß aggregation kinetics indicated that oxidized S100B was more effective in preventing aggregation, potentially linked to the oxidation of Met residues within the S100:Aß binding cleft that favors interactions. Using a cell culture model to analyze the S100B functions in a highly oxidative milieu, as in AD, we observed that Aß toxicity is rescued by the co-administration of oxidized S100B to a greater extent than by S100B. Additionally, results suggest a disrupted positive feedback loop involving S100B which is caused by its oxidation, leading to the downstream regulation of IL-17 and IFN-α2 expression as mediated by S100B.

Distinct Aß pathology in the olfactory bulb and olfactory deficits in a mouse model of Aß and α-syn co-pathology.

Several degenerative brain disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by the simultaneous appearance of amyloid-ß (Aß) and α-synuclein (α-syn) pathologies and symptoms that are similar, making it difficult to differentiate between these diseases. Until now, an accurate diagnosis can only be made by postmortem analysis. Furthermore, the role of α-syn in Aß aggregation and the arising characteristic olfactory impairments observed during the progression of these diseases is still not well understood. Therefore, we assessed Aß load in olfactory bulbs of APP-transgenic mice expressing APP695KM670/671NL and PSEN1L166P under the control of the neuron-specific Thy-1 promoter (referred to here as APPPS1) and APPPS1 mice co-expressing SNCAA30P (referred to here as APPPS1 × [A30P]aSYN). Furthermore, the olfactory capacity of these mice was evaluated in the buried food and olfactory avoidance test. Our results demonstrate an age-dependent increase in Aß load in the olfactory bulb of APP-transgenic mice that go along with exacerbated olfactory performance. Our study provides clear evidence that the presence of α-syn significantly diminished the endogenous and seed-induced Aß deposits and significantly ameliorated olfactory dysfunction in APPPS1 × [A30P]aSYN mice.

Nanomedicine Against Aß Aggregation by ß-Sheet Breaker Peptide Delivery: In Vitro Evidence.

The accumulation of amyloid ß (Aß) triggers a cascade of toxic events in Alzheimer's disease (AD). The KLVFF peptide can interfere with Aß aggregation. However, the peptide suffers from poor bioavailability and the inability to cross the blood-brain barrier. In this work, we study the possibility of adopting nanomedicine to overcome KLVFF limits in biodistribution. We produced new engineered polymeric nanoparticles (NPs), and we evaluated the cellular toxicity of these NPs and validated that KVLFF peptides released by NPs show the same promising effects on AD pathology. Our results revealed the successful generation of KVLFF loaded NPs that, without significant effects on cell heath, are even more potent in reversing Aß-induced pathologies compared to the free peptide. Therefore, NPs will significantly advance KVLFF treatment as a therapeutic option for AD.