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Intra-muscle fiber accumulation of ubiquitinated protein aggregates containing several conformationally modified proteins, including amyloid-β and phosphorylated tau, is characteristic of the pathologic phenotype of sporadic inclusion-body myositis (s-IBM), the most common progressive degenerative myopathy of older persons. Abnormalities of protein-degradation, involving both the 26S proteasome and autophagic-lysosomal pathways, were previously demonstrated in s-IBM muscle. NBR1 is a ubiquitin-binding scaffold protein importantly participating in autophagic degradation of ubiquitinated proteins. Whereas abnormalities of p62, a ubiquitin-binding protein, were previously described in s-IBM, abnormalities of NBR1 have not been reported in s-IBM. We have now identified in s-IBM muscle biopsies that NBR1, by: (a) immunohistochemistry, was strongly accumulated within s-IBM muscle-fiber aggregates, where it closely co-localized with p62, ubiquitin, and phosphorylated tau; (b) immunoblots, was increased threefold ( p < 0.001); and (c) immunoprecipitation, was associated with p62 and LC3. By real-time PCR, NBR1 mRNA was increased twofold ( p < 0.01). None of the various disease- and normal-control muscle biopsies had any NBR1 abnormality. In cultured human muscle fibers, NBR1 also physically associated with both p62 and LC3, and experimental inhibition of either the 26S proteasome or the lysosomal activity resulted in NBR1 increase. Our demonstration of NBR1 abnormalities in s-IBM provides further evidence that altered protein degradation pathways may be critically involved in the s-IBM pathogenesis. Accordingly, attempts to unblock defective protein degradation might be a therapeutic strategy for s-IBM patients. [ABSTRACT FROM AUTHOR]

Background: AD is associated with increases in lipid peroxidation and decreased antioxidant defense. Little is known about antioxidant defense of brain lipid rafts which are the site of APP processing. Oxidative damage to lipid rafts increases amyloid production. Lipid hydroperoxidases, glutathione peroxidase 4 (GPx4) and peroxiredoxin 6 (Prdx6) are potential detoxifying enzymes capable of reducing oxidized phospholipids and oxysterols within cellular membranes. We hypothesized that lipid hydroperoxidases would be reduced in ApoE4 carriers, which also have deficient cholesterol transport. To determine this, we investigated the status of the AD lipid raft by ApoE isoform in human frontal cortex. Method: Lipid rafts were isolated (Invent Biotechnologies; LR‐039) from postmortem AD (ApoE3,3, ApoE3,4, and ApoE4,4) and age‐matched controls (ApoE3,3) and were analyzed by western blot and enzymatic assay. Result: Lipid raft ApoE protein level of AD brains showed large decreases: 43% (Ctl vs AD3,3; p<0.01), 53% (Ctl vs AD3,4; p<0.001) and 70% (Ctl vs AD4,4; p<0.0001). Total cholesterol content of lipid rafts decreased 25% (Ctl vs AD; p<0.01). GPx4 protein of lipid rafts decreased 30% (Ctl vs AD3,3; p<0.01), 45% (Ctl vs AD3,4; p<0.0001) and 57% (Ctl vs AD4,4; p<0.001). AD brains from ApoE4,4 carriers had 36%(p<0.01) lower GPx4 localization than ApoE3,3. Prdx6 localization was not detected in the lipid rafts. Conclusion: Reductions in ApoE, total cholesterol, and GPx4 in the AD lipid raft suggests its vulnerability during AD. Furthermore, many of these decreases were ApoE isoform dependent, suggesting that antioxidant defense may differ by ApoE isoform. [ABSTRACT FROM AUTHOR]

Introduction: Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild-type and AD-transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments., Methods: We examined the γ-secretase modulator GSM-15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild-type mice were fed GSM-15606 during an 8-week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP)., Results: GSM-15606 decreased Aβ42 during nPM and DEP exposure without changing beta- or gamma-secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%., Discussion: These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM-15606 attenuation of Aβ42 may benefit human exposure to AirPoll., Highlights: Gamma-secretase modulator (GSM-15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM-15606 and other amyloid reduction treatments on secretase enzymes., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Ambient particulate matter (PM) smaller than 2.5 µm in diameter (PM 2.5 ) undergoes diurnal changes in chemical composition due to photochemical oxidation. In this study we examine the relationships between oxidative activity and inflammatory responses associated with these diurnal chemical changes. Because secondary PM contains a higher fraction of oxidized PM species, we hypothesized that PM 2.5 collected during afternoon hours would induce a greater inflammatory response than primary, morning PM 2.5 . Methods: Time-integrated aqueous slurry samples of ambient PM 2.5 were collected using a direct aerosol-into-liquid collection system during defined morning and afternoon time periods. PM 2.5 samples were collected for 5 weeks in the late summer (August-September) of 2016 at a central Los Angeles site. Morning samples, largely consisting of fresh primary traffic emissions (primary PM), were collected from 6-9am (am-PM 2.5 ), and afternoon samples were collected from 12-4pm (pm-PM 2.5 ), when PM composition is dominated by products of photochemical oxidation (secondary PM). The two diurnally phased PM 2.5 slurries (am- and pm-PM 2.5 ) were characterized for chemical composition and BV-2 microglia were assayed in vitro for oxidative and inflammatory gene responses. Results: Contrary to expectations, the am-PM 2.5 slurry had more proinflammatory activity than the pm-PM 2.5 slurry as revealed by nitric oxide (NO) induction, as well as the upregulation of proinflammatory cytokines IL-1β, IL-6, and CCL2 (MCP-1), as assessed by messenger RNA production. Conclusions: The diurnal differences observed in this study may be in part attributed to the greater content of transition metals and water-insoluble organic carbon (WIOC) of am-PM 2.5 (primary PM) vs. pm-PM 2.5 (secondary PM), as these two classes of compounds can increase PM 2.5 toxicity., Competing Interests: No competing interests were disclosed.