Age-dependent roles of peroxisomes in the hippocampus of a transgenic mouse model of Alzheimer’s disease

BACKGROUND: Alzheimer's Disease (AD) is a progressive neurodegenerative disease, especially affecting the hippocampus. Impairment of cognitive and memory functions is associated with amyloid beta-peptide-induced oxidative stress and alterations in lipid metabolism. In this scenario, the dual role of peroxisomes in producing and removing ROS, and their function in fatty acids beta-oxidation, may be critical. This work aims to investigating the possible involvement of peroxisomes in AD onset and progression, as studied in a transgenic mouse model, harboring the human Swedish familial AD mutation. We therefore characterized the peroxisomal population in the hippocampus, focusing on early, advanced, and late stages of the disease (3, 6, 9, 12, 18 months of age). Several peroxisome-related markers in transgenic and wild-type hippocampal formation were comparatively studied, by a combined molecular/immunohistochemical/ultrastructural approach. RESULTS: Our results demonstrate early and significant peroxisomal modifications in AD mice, compared to wild-type. Indeed, the peroxisomal membrane protein of 70 kDa and acyl-CoA oxidase 1 are induced at 3 months, possibly reflecting the need for efficient fatty acid beta-oxidation, as a compensatory response to mitochondrial dysfunction. The concomitant presence of oxidative damage markers and the altered expression of antioxidant enzymes argue for early oxidative stress in AD. During physiological and pathological brain aging, important changes in the expression of peroxisome-related proteins, also correlating with ongoing gliosis, occur in the hippocampus. These age- and genotype-based alterations, strongly dependent on the specific marker considered, indicate metabolic and/or numerical remodeling of peroxisomal population. CONCLUSIONS: Overall, our data support functional and biogenetic relationships linking peroxisomes to mitochondria and suggest peroxisomal proteins as biomarkers/therapeutic targets in pre-symptomatic AD

Proliferative response of foetal liver peroxisomes to clofibrate treatment of pregnant rats. A quantitative evaluation

Liver peroxisomes during prenatal development were studied by means of morphological and morphometric analysis in foetuses growing both in untreated and in clofibrate-treated rats. Pregnant rats were fed a standard diet (25 g/d) containing or not 0.8% clofibrate during the week preceding sacrifice and livers were excised from 13, 15, 17, 19 and 21-day old foetuses and newborn rats. The morphometric analysis of hepatocyte peroxisomes, performed by a semiautomatic method in specimens incubated with 3,3' diaminobenzidine, shows that the peroxisome volume density and average diameter in test animals were significantly increased over the control values. While the increase in the average diameter was roughly the same (X 1.4) at all examined stages, the volume density increased over the control values particularly in foetuses over 19d-old and in newborn rats; over the same period the peroxisome numerical density also significantly increased over the control values. Finally, the average diameters of peroxisome profiles in test rats showed a more dispersed distribution (SD 40%) than in control animals (SD 30%). These results demonstrate that clofibrate, given to rats during pregnancy, induces peroxisomal proliferation in the livers of their foetuses. Data are discussed in view of the models proposed for peroxisomal biogenesis

The features of acquired thrombotic thrombocytopenic purpura occurring at advanced age

Introduction: Acquired thrombotic thrombocytopenic purpura (aTTP) is a rare life-threatening thrombotic microangiopathy (TMA) affecting more frequently women of 30–50 years of age. There is scarce information on the clinical features of aTTP occurring in the elderly. Our goal was to evaluate the impact of an elderly-onset disease on the expression, severity and management of aTTP. Materials and methods: We performed a cross-sectional study of patients enrolled in the Milan TTP Registry (www.ttpdatabase.org) after a first acute episode of aTTP from January 2002 to March 2018. The aTTP diagnosis was suspected on the basis of the presence of thrombocytopenia and microangiopathic hemolytic anemia with no alternative causes, and was confirmed centrally by a severe plasma deficiency of ADAMTS13 activity (<10%). Triggers, clinical manifestations, laboratory parameters, management and outcome of the first acute events of elderly-onset aTTP patients (≥65 years) were compared with those of younger patients. Results: Among 143 eligible patients, 16 (11%) were elderly at onset. In comparison with younger cases they showed a lower rate of bleeding symptoms and severe anemia (30% and 18%), with a trend towards a higher rate of neurological and renal signs and symptoms. These patients were less frequently treated with plasma exchange and corticosteroids and more often with plasma infusion. No difference for gender, triggers and episode outcomes was observed. Conclusions: Older patients with aTTP differed from younger patients mainly for being treated less frequently with plasma exchange and corticosteroids, perhaps for the perceived risks associated with these treatments in the elderly

Search for new resonances decaying to a WW or ZZ boson and a Higgs boson in the ℓ+ℓ−bbˉ\ell^+ \ell^- b\bar b, ℓνbbˉ\ell \nu b\bar b, and ννˉbbˉ\nu\bar{\nu} b\bar b channels with pppp collisions at s=13\sqrt s = 13 TeV with the ATLAS detector

See paper for full list of authors, 18 pages (plus author list + cover pages: 36 pages total), 13 figures, 1 table. Submitted to PLB. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/EXOT-2015-18/International audienceA search is presented for new resonances decaying to a $W$ or $Z$ boson and a Higgs boson in the $\ell^+ \ell^- b\bar b$, $\ell\nu b\bar b$, and $\nu\bar{\nu} b\bar b$ channels in $pp$ collisions at $\sqrt s = 13$ TeV with the ATLAS detector at the Large Hadron Collider using a total integrated luminosity of 3.2 fb$^{-1}$. The search is conducted by looking for a localized excess in the $WH$/$ZH$ invariant or transverse mass distribution. No significant excess is observed, and the results are interpreted in terms of constraints on a simplified model based on a phenomenological Lagrangian of heavy vector triplets