| 1. |
- Boehm, Heike, et al.
(författare)
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Mapping the mechanics and macromolecular organization of hyaluronan-rich cell coats
- 2009
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Ingår i: Soft Matter. - : Royal Society of Chemistry (RSC). - 1744-6848 .- 1744-683X. ; 5:21, s. 4331-4337
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Tidskriftsartikel (refereegranskat)abstract
- The hyaluronan (HA)-rich pericellular coat (PCC) enveloping most mammalian cells plays a vital role in biological processes such as cell adhesion, proliferation, motility and embryogenesis. In particular its presence on chondrocytes, which live in the load-bearing cartilage, has a wide range of implications in diseases such as osteoarthritis, highlighting its mechanical role in living organisms. Despite its significance, the macromolecular organization of the cell coat remains speculative. In order to obtain a more detailed spatial picture of highly hydrated PCCs, we present two independent but complementary non-invasive techniques for the position-resolved analysis of the cell coat's mechanical and structural properties. Position-dependent microrheology provides a micromechanical map of the PCC that reveals a gradient of increasing elastic stiffness towards the plasma membrane on model rat chondrocyte cells (RCJ-P). This gradient can be correlated with the relative distribution of HA, which is inferred using an eGFP-labelled neurocan-binding domain, a small fluorescent molecule that binds to HA. The spatial variation of the HA concentration profile is consistent with the position-dependent elasticity. Combining these approaches sheds light on the molecular architecture of the PCC.
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| 2. |
- Craggs, Lucinda, et al.
(författare)
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Quantitative vascular pathology and phenotyping familial and sporadic cerebral small vessel diseases
- 2013
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Ingår i: Brain Pathology. - : Wiley. - 1015-6305 .- 1750-3639. ; 23:5, s. 547-557
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Tidskriftsartikel (refereegranskat)abstract
- We quantified vascular changes in the frontal lobe and basal ganglia of four inherited small vessel diseases (SVDs) including cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), pontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL), hereditary multi-infarct dementia of Swedish type (Swedish hMID), and hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). Vascular pathology was most severe in CADASIL, and varied with marginally greater severity in the basal ganglia compared to the frontal lobe. The overall sclerotic index values in frontal lobe were in the order CADASIL≥HERNS>PADMAL>Swedish hMID>sporadic SVD, and in basal ganglia CADASIL>HERNS>Swedish hMID>PADMAL> sporadic SVD. The subcortical white matter was almost always more affected than any gray matter. We observed glucose transporter-1 (GLUT-1) protein immunoreactivities were most affected in the white matter indicating capillary degeneration whereas collagen IV (COL4) immunostaining was increased in PADMAL cases in all regions and tissue types. Overall, GLUT-1:COL4 ratios were higher in the basal ganglia indicating modifications in capillary density compared to the frontal lobe. Our study shows that the extent of microvascular degeneration varies in these genetic disorders exhibiting common end-stage pathologies but is the most aggressive in CADASIL.
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| 3. |
- Sepulveda-Falla, Diego, et al.
(författare)
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A multifactorial model of pathology for age of onset heterogeneity in familial Alzheimer's disease.
- 2021
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Ingår i: Acta neuropathologica. - : Springer Science and Business Media LLC. - 1432-0533 .- 0001-6322. ; 141, s. 217-233
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Tidskriftsartikel (refereegranskat)abstract
- Presenilin-1 (PSEN1) mutations cause familial Alzheimer's disease (FAD) characterized by early age of onset (AoO). Examination of a large kindred harboring the PSEN1-E280A mutation reveals a range of AoO spanning 30years. The pathophysiological drivers and clinical impact of AoO variation in this population are unknown. We examined brains of 23 patients focusing on generation and deposition of beta-amyloid (Aβ) and Tau pathology profile. In 14 patients distributed at the extremes of AoO, we performed whole-exome capture to identify genotype-phenotype correlations. We also studied kinome activity, proteasome activity, and protein polyubiquitination in brain tissue, associating it with Tau phosphorylation profiles. PSEN1-E280A patients showed a bimodal distribution for AoO. Besides AoO, there were no clinical differences between analyzed groups. Despite the effect of mutant PSEN1 on production of Aβ, there were no relevant differences between groups in generation and deposition of Aβ. However, differences were found in hyperphosphorylated Tau (pTau) pathology, where early onset patients showed severe pathology with diffuse aggregation pattern associated with increased activation of stress kinases. In contrast, late-onset patients showed lesser pTau pathology and a distinctive kinase activity. Furthermore, we identified new protective genetic variants affecting ubiquitin-proteasome function in early onset patients, resulting in higher ubiquitin-dependent degradation of differentially phosphorylated Tau. In PSEN1-E280A carriers, altered γ-secretase activity and resulting Aβ accumulation are prerequisites for early AoO. However, Tau hyperphosphorylation pattern, and its degradation by the proteasome, drastically influences disease onset in individuals with otherwise similar Aβ pathology, hinting toward a multifactorial model of disease for FAD. In sporadic AD (SAD), a wide range of heterogeneity, also influenced by Tau pathology, has been identified. Thus, Tau-induced heterogeneity is a common feature in both AD variants, suggesting that a multi-target therapeutic approach should be used to treat AD.
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