Aß Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer's Disease.

We report a highly significant correlation in brain proteome changes between Alzheimers disease (AD) and CRND8 APP695NL/F transgenic mice. However, integrating protein changes observed in the CRND8 mice with co-expression networks derived from human AD, reveals both conserved and divergent module changes. For the most highly conserved module (M42, matrisome) we find many proteins accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of A ß ; in plaques and in CAA; further, recombinant MDK and PTN enhance A ß ; aggregation into amyloid. Multiple M42 proteins, annotated as heparan sulfate binding proteins, bind to fibrillar A ß 42 and a non-human amyloid fibril in vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart and islet amyloid polypeptide (IAPP) amyloid in the pancreas. Our findings establish several critical insights. Proteomic changes in modules observed in human AD brains define an A ß ; amyloid responsome that is well conserved from mouse model to human. Further, distinct amyloid structures may serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions. We hypothesize that this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

Gut microbiome and psychiatric disorders.

Several pieces of evidence show that gut microbiota can impact psychiatric disorders. However, no mechanism behind the relationship has been identified. Host genetics and their diets have a significant impact on the gut microbiota. More advanced studies are needed to find the mechanism and develop new therapeutic strategies.

Altered gut microbiome and autism like behavior are associated with parental high salt diet in male mice.

Neurodevelopmental disorders are conditions caused by the abnormal development of the central nervous system. Autism spectrum disorder (ASD) is currently the most common form of such disorders, affecting 1% of the population worldwide. Despite its prevalence, the mechanisms underlying ASD are not fully known. Recent studies have suggested that the maternal gut microbiome can have profound effects on neurodevelopment. Considering that the gut microbial composition is modulated by diet, we tested the hypothesis that ASD-like behavior could be linked to maternal diet and its associated gut dysbiosis. Therefore, we used a mouse model of parental high salt diet (HSD), and specifically evaluated social and exploratory behaviors in their control-fed offspring. Using 16S genome sequencing of fecal samples, we first show that (1) as expected, HSD changed the maternal gut microbiome, and (2) this altered gut microbiome was shared with the offspring. More importantly, behavioral analysis of the offspring showed hyperactivity, increased repetitive behaviors, and impaired sociability in adult male mice from HSD-fed parents. Taken together, our data suggests that parental HSD consumption is strongly associated with offspring ASD-like behavioral abnormalities via changes in gut microbiome.

Maternal elevated salt consumption and the development of autism spectrum disorder in the offspring.

Autism spectrum disorder (ASD) is a prevalent neurodevelopmental condition with no known etiology or cure. Several possible contributing factors, both genetic and environmental, are being actively investigated. Amongst these, maternal immune dysregulation has been identified as potentially involved in promoting ASD in the offspring. Indeed, ASD-like behaviors have been observed in studies using the maternal immune activation mouse model. Furthermore, recent studies have shed light on maternal dietary habits and their impact on the gut microbiome as factors possibly facilitating ASD. However, most of these studies have been limited to the effects of high fat and/or high sugar. More recent data, however, have shown that elevated salt consumption has a significant effect on the immune system and gut microbiome, often resulting in gut dysbiosis and induction of pro-inflammatory pathways. Specifically, high salt alters the gut microbiome and induces the differentiation of T helper-17 cells that produce pro-inflammatory cytokines such as interleukin-17 and interleukin-23. Moreover, elevated salt can also reduce the differentiation of regulatory T cells that help maintaining a balanced immune system. While in the innate immune system, high salt can cause over activation of M1 pro-inflammatory macrophages and downregulation of M2 regulatory macrophages. These changes to the immune system are alarming because excessive consumption of salt is a documented worldwide problem. Thus, in this review, we discuss recent findings on high salt intake, gut microbiome, and immune system dysregulation while proposing a hypothesis to link maternal overconsumption of salt and children's ASD.