Apolipoprotein E ε4/4 genotype limits response to dietary induction of hyperhomocysteinemia and resulting inflammatory signaling

Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind Alzheimer’s disease. Apolipoprotein E (ApoE) is a lipid transporting lipoprotein found within the brain and periphery. The APOE ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease and is a risk factor for VCID. Our lab has previously utilized a dietary model of hyperhomocysteinemia (HHcy) to induce VCID pathology and cognitive deficits in mice. This diet induces perivascular inflammation through cumulative oxidative damage leading to glial mediated inflammation and blood brain barrier breakdown. Here, we examine the impact of ApoE ε4 compared to ε3 alleles on the progression of VCID pathology and inflammation in our dietary model of HHcy. We report a significant resistance to HHcy induction in ε4 mice, accompanied by a number of related differences related to homocysteine (Hcy) metabolism and methylation cycle, or 1-C, metabolites. There were also significant differences in inflammatory profiles between ε3 and ε4 mice, as well as significant reduction in Serpina3n, a serine protease inhibitor associated with ApoE ε4, expression in ε4 HHcy mice relative to ε4 controls. Finally, we find evidence of pervasive sex differences within both genotypes in response to HHcy induction.

MSR1 and NEP Are Correlated with Alzheimer’s Disease Amyloid Pathology and Apolipoprotein Alterations

Background: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. Objective: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aβ 1 - 42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer’s disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). Methods: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aβ 1 - 42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex’s multiplex technology. Brain MSR1, APOE, and CLU (ApoJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. Results: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aβ 1 - 42, ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. Conclusion: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aβ 1 - 42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages.

HARM revisited: Etiology of subarachnoid hyperintensities in brain FLAIR MRI

Background: The hyperintense acute reperfusion marker (HARM) describes a phenomenon with a hyperintense signal in the subarachnoid space in Fluid-Attenuated Inversion Recovery (FLAIR) magnetic resonance imaging (MRI) sequences, presumably based on blood–brain barrier breakdown in acute stroke with reperfusion. However, this imaging phenomenon was described in other medical conditions. Aim: Determination of the prevalence and associated clinical findings of this phenomenon in a large sample of patients with different neurological conditions. Methods: This is retrospective, single-center, observational study of 23,948 cerebral MRIs acquired in a Neurological University Clinic over 5 years. The prevalence of HARM, the underlying diagnosis, and damage pattern were examined by chart analysis; MRI was analyzed regarding the type of acute lesions, extent of microangiopathic lesions, and whether gadolinium-based contrast agent (GBCA) was given. Results: Among the MRI data, 84 images (0.35%) from 61 patients were HARM-positive without a subarachnoid signal abnormality in any other sequence. Etiologies were heterogeneous; 35 patients had a cerebrovascular disease (CVD; 19 patients received recanalization therapy), 12 patients had an inflammatory central nervous system (CNS) disease and 14 patients had epilepsy. GBCA was applied to 64% of the patients. Conclusion: HARM was a rare radiological finding in a range of different neurological pathologies, not limited to stroke, or to previous reperfusion therapy and was not dependent on previous GBCA administration. Our data suggest that the term is too narrow in terms of the concepts of the underlying pathology. We propose to use the term FLAIR Subarachnoid Hyperintensity (“FLASH”) phenomenon which might better reflect the observation that the radiological sign can be associated with a variety of central neurological conditions without a straightforward association with therapy.

The gut commensal Bacteroides vulgatus mpk reduces Candida albicans pathogenicity towards epithelial cells

The human body is colonized by various microbes, among them the yeast Candida albicans. Mostly harmless, this opportunist causes also disease, ranging from superficial infections to sepsis. Risk factors are disturbed host defenses, mucosal barrier breakdown, and antibiotic-induced dysbiosis. Hence, residing bacteria are important to protect from Candida-mediated damage or inflammation. Bacteroides vulgatus mpk, e.g., is described as positively immunomodulatory in mouse models of inflammatory bowel disease, but its effect on the mycobiota is unknown. In this study we aimed to determine if B. vulgatus mpk affects C. albicans pathogenicity. Therefore, intestinal and oral epithelial cellswere pre-infectedin vitrowith B. vulgatus mpk and then challenged with C. albicans SC5314. The role of soluble factors was investigated by spatial separation or use of Bacteroides-conditioned medium (BCM). Preincubation of host cells with B. vulgatus mpk strongly reduced C. albicans-mediated damage while fungal burden and hyphal length were unaffected by the bacterium. The protective effect did not depend on direct contact of Bacteroidesto host cellsor Candida and could be mimicked using BCM. Contact independency suggests that diffusible factors modulate host cell susceptibility. Ongoing experiments aim to identifykey soluble Bacteroides mediators as well as subsequent host cell signaling. Additionally, co-colonization experiments of germ-free mice are planned to investigate B. vulgatus mpk’s potential to mediate colonization resistance towards C. albicans. This will contribute to our understanding of how commensal bacteria affect C. albicans and host protection.

Microenvironmental Variations After Blood-Brain Barrier Breakdown in Traumatic Brain Injury

Traumatic brain injury (TBI) is linked to several pathologies. The blood-brain barrier (BBB) breakdown is considered to be one of the initial changes. Further, the microenvironmental alteration following TBI-induced BBB breakdown can be multi-scaled, constant, and dramatic. The microenvironmental variations after disruption of BBB includes several pathological changes, such as cerebral blood flow (CBF) alteration, brain edema, cerebral metabolism imbalances, and accumulation of inflammatory molecules. The modulation of the microenvironment presents attractive targets for TBI recovery, such as reducing toxic substances, inhibiting inflammation, and promoting neurogenesis. Herein, we briefly review the pathological alterations of the microenvironmental changes following BBB breakdown and outline potential interventions for TBI recovery based on microenvironmental modulation.

Tyrosine phosphorylation of S1PR1 leads to chaperone BiP-mediated import to the endoplasmic reticulum

Cell surface G protein–coupled receptors (GPCRs), upon agonist binding, undergo serine–threonine phosphorylation, leading to either receptor recycling or degradation. Here, we show a new fate of GPCRs, exemplified by ER retention of sphingosine-1-phosphate receptor 1 (S1PR1). We show that S1P phosphorylates S1PR1 on tyrosine residue Y143, which is associated with recruitment of activated BiP from the ER into the cytosol. BiP then interacts with endocytosed Y143-S1PR1 and delivers it into the ER. In contrast to WT-S1PR1, which is recycled and stabilizes the endothelial barrier, phosphomimicking S1PR1 (Y143D-S1PR1) is retained by BiP in the ER and increases cytosolic Ca2+ and disrupts barrier function. Intriguingly, a proinflammatory, but non-GPCR agonist, TNF-α, also triggered barrier-disruptive signaling by promoting S1PR1 phosphorylation on Y143 and its import into ER via BiP. BiP depletion restored Y143D-S1PR1 expression on the endothelial cell surface and rescued canonical receptor functions. Findings identify Y143-phosphorylated S1PR1 as a potential target for prevention of endothelial barrier breakdown under inflammatory conditions.

The Health Hazards of Volcanoes: First Evidence of Neuroinflammation in the Hippocampus of Mice Exposed to Active Volcanic Surroundings

Neuroinflammation is a process related to the onset of neurodegenerative diseases; one of the hallmarks of this process is microglial reactivation and the secretion by these cells of proinflammatory cytokines such as TNFα. Numerous studies report the relationship between neuroinflammatory processes and exposure to anthropogenic air pollutants, but few refer to natural pollutants. Volcanoes are highly inhabited natural sources of environmental pollution that induce changes in the nervous system, such as reactive astrogliosis or the blood-brain barrier breakdown in exposed individuals; however, no neuroinflammatory event has been yet defined. To this purpose, we studied resting microglia, reactive microglia, and TNFα production in the brains of mice chronically exposed to an active volcanic environment on the island of São Miguel (Azores, Portugal). For the first time, we demonstrate a proliferation of microglial cells and an increase in reactive microglia, as well an increase in TNFα secretion, in the central nervous system of individuals exposed to volcanogenic pollutants.