312 research outputs found
Variability in the type and layer distribution of cortical A beta pathology in familial Alzheimer's disease
Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD
Proton Pump Activity of Mitochondria-rich Cells : The Interpretation of External Proton-concentration Gradients
We have hypothesized that a major role of the apical H+-pump in mitochondria-rich (MR) cells of amphibian skin is to energize active uptake of Clâ via an apical Clâ/HCO3â-exchanger. The activity of the H+ pump was studied by monitoring mucosal [H+]-profiles with a pH-sensitive microelectrode. With gluconate as mucosal anion, pH adjacent to the cornified cell layer was 0.98 Âą 0.07 (mean Âą SEM) pH-units below that of the lightly buffered bulk solution (pH = 7.40). The average distance at which the pH-gradient is dissipated was 382 Âą 18 Îźm, corresponding to an estimated âunstirred layerâ thickness of 329 Âą 29 Îźm. Mucosal acidification was dependent on serosal pCO2, and abolished after depression of cellular energy metabolism, confirming that mucosal acidification results from active transport of H+. The [H+] was practically similar adjacent to all cells and independent of whether the microelectrode tip was positioned near an MR-cell or a principal cell. To evaluate [H+]-profiles created by a multitude of MR-cells, a mathematical model is proposed which assumes that the H+ distribution is governed by steady diffusion from a number of point sources defining a set of particular solutions to Laplace's equation. Model calculations predicted that with a physiological density of MR cells, the [H+] profile would be governed by so many sources that their individual contributions could not be experimentally resolved. The flux equation was integrated to provide a general mathematical expression for an external standing [H+]âgradient in the unstirred layer. This case was treated as free diffusion of protons and proton-loaded buffer molecules carrying away the protons extruded by the pump into the unstirred layer; the expression derived was used for estimating stationary proton-fluxes. The external [H+]-gradient depended on the mucosal anion such as to indicate that base (HCO3â) is excreted in exchange not only for Cl â, but also for Brâ and Iâ, indicating that the active fluxes of these anions can be attributed to mitochondria-rich cells
Age-related collagen turnover of the interstitial matrix and basement membrane: Implications of age- and sex-dependent remodeling of the extracellular matrix
The extracellular matrix (ECM) plays a vital role in maintaining normal tissue function. Collagens are major components of the ECM and there is a tight equilibrium between degradation and formation of these proteins ensuring tissue health and homeostasis. As a consequence of tissue turnover, small collagen fragments are released into the circulation, which act as important biomarkers in the study of certain tissue-related remodeling factors in health and disease. The aim of this study was to establish an age-related collagen turnover profile of the main collagens of the interstitial matrix (type I and III collagen) and basement membrane (type IV collagen) in healthy men and women. By using well-characterized competitive ELISA-assays, we assessed specific fragments of degraded (C1M, C3M, C4M) and formed (PINP, Pro-C3, P4NP7S) type I, III and IV collagen in serum from 617 healthy men and women ranging in ages from 22 to 86. Subjects were divided into 5-year age groups according to their sex and age. Groups were compared using Kruskal-Wallis adjusted for Dunn's multiple comparisons test and Mann-Whitney t-test. Age-specific changes in collagen turnover was most profound for type I collagen. PINP levels decreased in men with advancing age, whereas in women, the level decreased in early adulthood followed by an increase around the age of menopause (age 40-60). Sex-specific changes in type I, III and IV collagen turnover was present at the age around menopause (age 40-60) with women having an increased turnover. In summary, collagen turnover is affected by age and sex with the interstitial matrix and the basement membrane being differently regulated. The observed changes needs to be accounted for when measuring ECM related biomarkers in clinical studies
Cathepsin-S degraded decorin are elevated in fibrotic lung disorders - development and biological validation of a new serum biomarker
Familial Alzheimer's Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis
Mutations in presenilin 1 (PSEN1) or presenilin 2 (PSEN2), the catalytic subunit of Îł-secretase, cause familial Alzheimerâs disease (fAD). We hypothesized that mutations in PSEN1 reduce Notch signaling and alter neurogenesis. Expression data from developmental and adult neurogenesis show relative enrichment of Notch and Îł-secretase expression in stem cells, whereas expression of APP and β-secretase is enriched in neurons. We observe premature neurogenesis in fAD iPSCs harboring PSEN1 mutations using two orthogonal systems: cortical differentiation in 2D and cerebral organoid generation in 3D. This is partly driven by reduced Notch signaling. We extend these studies to adult hippocampal neurogenesis in mutation-confirmed postmortem tissue. fAD cases show mutation-specific effects and a trend toward reduced abundance of newborn neurons, supporting a premature aging phenotype. Altogether, these results support altered neurogenesis as a result of fAD mutations and suggest that neural stem cell biology is affected in aging and disease
Association of MAPT haplotypeâtagging polymorphisms with cerebrospinal fluid biomarkers of Alzheimer's disease: A preliminary study in a Croatian cohort
Introduction:
Alzheimer's disease (AD) is the world leading cause of dementia. Early detection of AD is essential for faster and more efficacious usage of therapeutics and preventive measures. Even though it is well known that one Îľ4 allele of apolipoprotein E gene increases the risk for sporadic AD five times, and that two Îľ4 alleles increase the risk 20 times, reliable genetic markers for AD are not yet available. Previous studies have shown that microtubuleâassociated protein tau (MAPT) gene polymorphisms could be associated with increased risk for AD.
Methods:
The present study included 113 AD patients and 53 patients with mild cognitive impairment (MCI), as well as nine healthy controls (HC) and 53 patients with other primary causes of dementia. The study assessed whether six MAPT haplotypeâtagging polymorphisms (rs1467967, rs242557, rs3785883, rs2471738, delâIn9, and rs7521) and MAPT haplotypes are associated with AD pathology, as measured by cerebrospinal fluid (CSF) AD biomarkers amyloid β1â42 (Aβ1â42), total tau (tâtau), tau phosphorylated at epitopes 181 (pâtau181), 199 (pâtau199), and 231 (pâtau231), and visininâlike protein 1 (VILIPâ1).
Results:
Significant increases in tâtau and pâtau CSF levels were found in patients with AG and AA MAPT rs1467967 genotype, CC MAPT rs2471738 genotype and in patients with H1H2 or H2H2 MAPT haplotype.
Conclusions:
These results indicate that MAPT haplotypeâtagging polymorphisms and MAPT haplotypes should be further tested as potential genetic biomarkers of AD
Blood-based extracellular matrix biomarkers are correlated with clinical outcome after PD-1 inhibition in patients with metastatic melanoma
Background Immune checkpoint inhibitors that target
the programmed cell death protein 1 (PD-1) receptor
induce a response in only a subgroup of patients with
metastatic melanoma. Previous research suggests that
transforming growth factor beta signaling and a collagenrich peritumoral stroma (tumor fibrosis), may negatively
interfere with the interaction between T cells and tumor
cells and thereby contribute to resistance mechanisms by
immune-exclusion, while increased tumor infiltration of
M1-like macrophages enhances T cell activity. Hence, the
current study aimed to assess the relationship between
blood-based markers of collagen or vimentin turnover
(reflecting M1 macrophage activity) and clinical outcome in
patients with metastatic melanoma after PD-1 inhibition.
Methods Patients with metastatic melanoma who
were treated with anti-PD-1 monotherapy between May
2016 and March 2019 were included in a prospective
observational study. N-terminal pro-peptide of type III
collagen (PRO-C3) cross-linked N-terminal pro-peptides
of type III collagen (PC3X), matrix metalloprotease (MMP)-
degraded type III (C3M) and type IV collagen (C4M),
granzyme B-degraded type IV collagen and citrullinated
and MMP-degraded vimentin (VICM) were measured with
immunoassays in serum before (n=107), and 6weeks
after the first administration of immunotherapy (n=94). The
association between biomarker levels and overall survival
(OS) or progression-free survival (PFS) was assessed.
Results Multivariate Cox regression analysis identified
high baseline PRO-C3 (Q4) and PC3X (Q4) as independent
variables of worse PFS (PRO-C3: HR=1.81, 95% CI=1.06
to 3.10, p=0.030 and PC3X: HR=1.86, 95% CI=1.09
to 3.18, p=0.023). High baseline PRO-C3 was also
independently related to worse OS (HR=2.08, 95%
CI=1.06 to 4.09, p=0.035), whereas a high C3M/PRO-C3
ratio was related to improved OS (HR=0.42, 95% CI=0.20
to 0.90, p=0.025). An increase in VICM (p<0.0001; in 56%
of the patients) was observed after 6weeks of treatment,
and an increase in VICM was independently associated
with improved OS (HR=0.28, 95% CI=0.10 to 0.77,
p=0.014).
Conclusions Blood-based biomarkers reflecting
excessive type III collagen turnover were associated with
worse OS and PFS after PD-1 inhibition in metastatic
melanoma. Moreover, an increase in VICM levels after
6weeks of treatment was associated with improved OS These findings suggest that type III collagen and vimentin
turnover contribute to resistance/response mechanisms of
PD-1 inhibitors and hold promise of assessing extracellular
matrix-derived and stroma-derived components to predict
immunotherapy response
Plasma amyloid-β ratios in autosomal dominant Alzheimer's disease: the influence of genotype.
In-vitro studies of autosomal dominant Alzheimer's disease implicate longer amyloid-beta peptides in disease pathogenesis, however less is known about the behaviour of these mutations in-vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at-risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-beta42:38, 42:40 and 38:40 ratios between presenilin1 and amyloid precursor protein carriers. We examined the relationship between plasma and in-vitro models of amyloid-beta processing and tested for associations with parental age at onset. 39 participants were mutation carriers (28 presenilin1 and 11 amyloid precursor protein). Age- and sex-adjusted models showed marked differences in plasma amyloid-beta between genotypes: higher amyloid-beta42:38 in presenilin1 versus amyloid precursor protein (pâ<â0.001) and non-carriers (pâ<â0.001); higher amyloid-beta38:40 in amyloid precursor protein versus presenilin1 (pâ<â0.001) and non-carriers (pâ<â0.001); while amyloid-beta42:40 was higher in both mutation groups compared to non-carriers (both pâ<â0.001). Amyloid-beta profiles were reasonably consistent in plasma and cell lines. Within presenilin1, models demonstrated associations between amyloid-beta42:38, 42:40 and 38:40 ratios and parental age at onset. In-vivo differences in amyloid-beta processing between presenilin1 and amyloid precursor protein carriers provide insights into disease pathophysiology, which can inform therapy development
The PEP survey: clustering of infrared-selected galaxies and structure formation at z~2 in the GOODS South
ABRIDGED-This paper presents the first direct estimate of the 3D clustering
properties of far-infrared sources up to z~3. This has been possible thanks to
the Pacs Evolutionary Probe (PEP) survey of the GOODS South field performed
with the PACS instrument onboard the Herschel Satellite. An analysis of the
two-point correlation function over the whole redshift range spanned by the
data reports for the correlation length, r_0~6.3 Mpc and r_0~6.7 Mpc,
respectively at 100um and 160um, corresponding to dark matter halo masses
M>~10^{12.4} M_sun. Objects at z~2 instead seem to be more strongly clustered,
with r_0~19 Mpc and r_0~17 Mpc in the two considered PACS channels. This
dramatic increase of the correlation length between z~1 and z~2 is connected
with the presence of a wide, M>~10^{14} M_sun, filamentary structure which
includes more than 50% of the sources detected at z~2. An investigation of the
properties of such sources indicates the possibility for boosted star-forming
activity in those which reside within the overdense environment with respect of
more isolated galaxies found in the same redshift range. Lastly, we also
present our results on the evolution of the relationship between luminous and
dark matter in star-forming galaxies between z~1 and z~2. We find that the
increase of (average) stellar mass in galaxies between z~1 and z~2 is
about a factor 10 lower than that of the dark matter haloes hosting such
objects ([z~1]/[z~2] ~ 0.4 vs M_{halo}[z~1]/M_{halo}[z~2] ~ 0.04). Our
findings agree with the evolutionary picture of downsizing whereby massive
galaxies at z~2 were more actively forming stars than their z~1 counterparts,
while at the same time contained a lower fraction of their mass in the form of
luminous matter.Comment: 14 pages, 8 figures, MNRAS accepte
Serum type XVI collagen is associated with colorectal cancer and ulcerative colitis indicating a pathological role in gastrointestinal disorders
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