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  • 1
    In: Acta Neuropathologica Communications, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2020-12)
    Abstract: Cerebral amyloid angiopathy (CAA) is characterized by the deposition of the amyloid β (Aβ) protein in the cerebral vasculature and poses a major risk factor for the development of intracerebral haemorrhages (ICH). However, only a minority of patients with CAA develops ICH (CAA-ICH), and to date it is unclear which mechanisms determine why some patients with CAA are more susceptible to haemorrhage than others. We hypothesized that an imbalance between matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) contributes to vessel wall weakening. MMP9 plays a role in the degradation of various components of the extracellular matrix as well as of Aβ and increased MMP9 expression has been previously associated with CAA. TIMP3 is an inhibitor of MMP9 and increased TIMP3 expression in cerebral vessels has also been associated with CAA. In this study, we investigated the expression of MMP9 and TIMP3 in occipital brain tissue of CAA-ICH cases ( n  = 11) by immunohistochemistry and compared this to the expression in brain tissue of CAA cases without ICH (CAA-non-haemorrhagic, CAA-NH, n  = 18). We showed that MMP9 expression is increased in CAA-ICH cases compared to CAA-NH cases. Furthermore, we showed that TIMP3 expression is increased in CAA cases compared to controls without CAA, and that TIMP3 expression is reduced in a subset of CAA-ICH cases compared to CAA-NH cases. In conclusion, in patients with CAA, a disbalance in cerebrovascular MMP9 and TIMP3 expression is associated with CAA-related ICH.
    Type of Medium: Online Resource
    ISSN: 2051-5960
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2020
    detail.hit.zdb_id: 2715589-4
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  • 2
    In: BMC Biology, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2021-12)
    Abstract: The skeletal muscle plays a central role in glucose homeostasis through the uptake of glucose from the extracellular medium in response to insulin. A number of factors are known to disrupt the normal response to insulin leading to the emergence of insulin resistance (IR). Advanced age and a high-fat diet are factors that increase the susceptibility to IR, with lipid accumulation in the skeletal muscle being a key driver of this phenomenon. It is debated, however, whether lipid accumulation arises due to dietary lipid overload or from a decline of mitochondrial function. To gain insights into the interplay of diet and age in the flexibility of muscle lipid and glucose handling, we combined lipidomics, proteomics, mitochondrial function analysis and computational modelling to investigate young and aged mice on a low- or high-fat diet (HFD). Results As expected, aged mice were more susceptible to IR when given a HFD than young mice. The HFD induced intramuscular lipid accumulation specifically in aged mice, including C18:0-containing ceramides and diacylglycerols. This was reflected by the mitochondrial β-oxidation capacity, which was upregulated by the HFD in young, but not in old mice. Conspicuously, most β-oxidation proteins were upregulated by the HFD in both groups, but carnitine palmitoyltransferase 1B (CPT1B) declined in aged animals. Computational modelling traced the flux control mostly to CPT1B, suggesting a CPT1B-driven loss of flexibility to the HFD with age. Finally, in old animals, glycolytic protein levels were reduced and less flexible to the diet. Conclusion We conclude that intramuscular lipid accumulation and decreased insulin sensitivity are not due to age-related mitochondrial dysfunction or nutritional overload alone, but rather to their combined effects. Moreover, we identify CPT1B as a potential target to counteract age-dependent intramuscular lipid accumulation and thereby IR.
    Type of Medium: Online Resource
    ISSN: 1741-7007
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2133020-7
    SSG: 12
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  • 3
    In: The FEBS Journal, Wiley, Vol. 288, No. 7 ( 2021-04), p. 2257-2277
    Abstract: Dietary protein restriction has been demonstrated to improve metabolic health under various conditions. However, the relevance of ageing and age‐related decline in metabolic flexibility on the effects of dietary protein restriction has not been addressed. Therefore, we investigated the effect of short‐term dietary protein restriction on metabolic health in young and aged mice. Young adult (3 months old) and aged (18 months old) C57Bl/6J mice were subjected to a 3‐month dietary protein restriction. Outcome parameters included fibroblast growth factor 21 (FGF21) levels, muscle strength, glucose tolerance, energy expenditure (EE) and transcriptomics of brown and white adipose tissue (WAT). Here, we report that a low‐protein diet had beneficial effects in aged mice by reducing some aspects of age‐related metabolic decline. These effects were characterized by increased plasma levels of FGF21, browning of subcutaneous WAT, increased body temperature and EE, while no changes were observed in glucose homeostasis and insulin sensitivity. Moreover, the low‐protein diet used in this study was well‐tolerated in aged mice indicated by the absence of adverse effects on body weight, locomotor activity and muscle performance. In conclusion, our study demonstrates that a short‐term reduction in dietary protein intake can impact age‐related metabolic health alongside increased FGF21 signalling, without negatively affecting muscle function. These findings highlight the potential of protein restriction as a strategy to induce EE and browning of WAT in aged individuals.
    Type of Medium: Online Resource
    ISSN: 1742-464X , 1742-4658
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2172518-4
    SSG: 12
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