Enteric α-synuclein impairs intestinal epithelial barrier through caspase-1-inflammasome signaling in Parkinson’s disease before brain pathology

AbstractsBowel inflammation, impaired intestinal epithelial barrier (IEB), and gut dysbiosis could represent early events in Parkinson’s disease (PD). This study examined, in a descriptive manner, the correlation among enteric α-synuclein, bowel inflammation, impairments of IEB and alterations of enteric bacteria in a transgenic (Tg) model of PD before brain pathology. Human A53T α-synuclein Tg mice were sacrificed at 3, 6, and 9 months of age to evaluate concomitance of enteric inflammation, IEB impairments, and enteric bacterial metabolite alterations during the early phases of α-synucleinopathy. The molecular mechanisms underlying the interplay between α-synuclein, activation of immune/inflammatory responses and IEB alterations were investigated with in vitro experiments in cell cultures. Tg mice displayed an increase in colonic levels of IL-1β, TNF, caspase-1 activity and enteric glia activation since 3 months of age. Colonic TLR-2 and zonulin-1 expression were altered in Tg mice as compared with controls. Lipopolysaccharide levels were increased in Tg animals at 3 months, while fecal butyrate and propionate levels were decreased. Co-treatment with lipopolysaccharide and α-synuclein promoted IL-1β release in the supernatant of THP-1 cells. When applied to Caco-2 cells, the THP-1-derived supernatant decreased zonulin-1 and occludin expression. Such an effect was abrogated when THP-1 cells were incubated with YVAD (caspase-1 inhibitor) or when Caco-2 were incubated with anakinra, while butyrate incubation did not prevent such decrease. Taken together, early enteric α-synuclein accumulation contributes to compromise IEB through the direct activation of canonical caspase-1-dependent inflammasome signaling. These changes could contribute both to bowel symptoms as well as central pathology.

Associations Between Atrial Arrhythmias and Brain Amyloid Deposition: The ARIC-PET Study

The aim of this study is to determine if there is an association between atrial arrhythmias and brain amyloid-β (Aβ), measured on florbetapir (FBP) PET. 346 nondemented participants from the Atherosclerosis Risk in Communities study underwent FBP-PET, 185 also wore Zio® XT Patch. The associations between global cortical Aβ (> 1.2 standardized uptake value ratio) and history of atrial fibrillation, zio-defined atrial tachycardia and premature atrial contractions, each, were evaluated. Among nondemented community-dwelling older adults, we did not find an association between atrial arrhythmias and Aβ. Other brain pathology may underlie the association described between atrial arrhythmias and cognition.

Revisiting the grammar of Tau aggregation and pathology formation: how new insights from brain pathology are shaping how we study and target Tauopathies

We discuss novel approaches for embracing and reproducing complexity of Tau pathology required for developing disease-relevant diagnostics and effective therapies.

Decrowding Expansion Pathology: Unmasking Previously Invisible Nanostructures and Cells in Intact Human Brain Pathology Specimens

Proteins are densely packed in cells and tissues, where they form complex nanostructures. Expansion microscopy (ExM) variants have been used to separate proteins from each other in preserved biospecimens, improving antibody access to epitopes. Here we present an ExM variant, decrowding expansion pathology (dExPath), which can expand proteins away from each other in human brain pathology specimens, including formalin-fixed paraffin-embedded (FFPE) clinical specimens. Immunostaining of dExPath-expanded specimens reveals, with nanoscale precision, previously unobserved cellular structures, as well as more continuous patterns of staining. This enhanced molecular staining results in observation of previously invisible disease marker-positive cell populations in human glioma specimens, with potential implications for tumor aggressiveness. dExPath results in improved fluorescence signals even as it eliminates lipofuscin-associated autofluorescence. Thus, this form of expansion-mediated protein decrowding may, through improved epitope access for antibodies, render immunohistochemistry more powerful in clinical science and diagnosis.

Why Does Cognitive Reserve Align With Modern Western Ideals of Success? Theoretical & Methodological Proposals

Cognitive reserve (CR) is a framework that investigates discrepancies between brain pathology and cognitive decline. In explaining why individuals with similar levels of brain pathology display different levels of functional impairment, CR research focuses on factors that resemble modern, Western ideals of success: greater education, professional achievement, a self-directed life, and physically and intellectually stimulating leisure time. This theoretical paper documents this alignment between CR and modern, Western ideals of success to hypothesize different mechanisms by which CR may operate. The focus in the CR literature has been on investigating and operationalizing the direct cognitive changes that come from intellectual cultivation, and the native abilities that are hypothesized to produce differences in both education and cognitive outcomes. This paper argues that an attention to CR’s relationship to current definitions of success presents alternative hypotheses about the mechanisms by which CR operates. Specifically, the paper outlines two potential mechanisms and frames alternative means of studying them: First, does the accrual of CR simply follow from being successful in conventional ways because of the material benefits of wealth and stability that success brings? Second, does a lack of success carry cognitive risks solely because of material deprivation, or are there additional psychosocial penalties that come from living a non-normative life—especially when that is not of one’s choosing? This paper proposes both cross-cultural and intersectional methods to begin to better understand the relationship between normative success and cognitive health.