Epidemiological evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) decrease the risk for Alzheimer's disease (AD). Certain NSAIDs can activate the peroxisome proliferator-activated ...receptor-γ (PPARγ), which is a nuclear transcriptional regulator. Here we show that PPARγ depletion potentiates β-secretase β-site amyloid precursor protein cleaving enzyme (BACE1) mRNA levels by increasing BACE1 gene promoter activity. Conversely, overexpression of PPARγ, as well as NSAIDs and PPARγ activators, reduced BACE1 gene promoter activity. These results suggested that PPARγ could be a repressor of BACE1. We then identified a PPARγ responsive element (PPRE) in the BACE1 gene promoter. Mutagenesis of the PPRE abolished the binding of PPARγ to the PPRE and increased BACE1 gene promoter activity. Furthermore, proinflammatory cytokines decreased PPARγ gene transcription, and this effect was supressed by NSAIDs. We also demonstrate that in vivo treatment with PPARγ agonists increased PPARγ and reduced BACE1 mRNA and intracellular β-amyloid levels. Interestingly, brain extracts from AD patients showed decreased PPARγ expression and binding to PPRE in the BACE1 gene promoter. Our data strongly support a major role of PPARγ in the modulation of amyloid-β generation by inflammation and suggest that the protective mechanism of NSAIDs in AD involves activation of PPARγ and decreased BACE1 gene transcription.
The immunocytochemical distribution of the neuronal form of nitric oxide synthase (nNOS) was compared with neuropathological changes and with cell death related DNA damage (as revealed by in situ end ...labeling, ISEL) in the hippocampal formation and entorhinal cortex of 12 age-matched control subjects and 12 Alzheimer's disease (AD) patients. Unlike controls, numerous nNOS-positive reactive astrocytes were found in AD patients around β-amyloid plaques in CA1 and subiculum and at the places of clear and overt neuron loss, particularly in the entorhinal cortex layer II and CA4. This is the first evidence of nNOS-like immunoreactivity in reactive astrocytes in AD. In contrast to controls, in all but one AD subject, large numbers of ISEL-positive neuronal nuclei and microglial cells were found in the CA1 and CA4 regions and subiculum. Semiquantitative analysis showed that neuronal DNA fragmentation in AD match with the distribution of nNOS-expressing reactive astroglial cells in CA1 (r = 0.74, P < 0.01) and CA4 (r = 0.58, P < 0.05). A portion of the nNOS-positive CA2/CA3 pyramidal neurons was found to be spared even in the most affected hippocampi. A significant inverse correlation between nNOS expression and immunoreactivity to abnormally phosphorylated tau proteins (as revealed by AT8 monoclonal antibody) in perikarya of these CA2/3 neurons (r = −0.85, P < 0.01) suggests that nNOS expression may provide selective resistance to neuronal degeneration in AD. In conclusion, our results imply that an upregulated production of NO by reactive astrocytes may play a key role in the pathogenesis of AD.
Alzheimer's disease (AD) is characterized by impaired protein homeostasis leading to amyloid-β peptide (Aβ) amyloidosis. Amyloid precursor protein (APP) knock-in mice exhibit robust Aβ pathology, ...providing possibilities to determine its effect on protein homeostasis including autophagy. Here we compared human AD postmortem brain tissue with brains from two different types of
knock-in mice,
and
mice, exhibiting AD-like pathology. In AD postmortem brains, p62 levels are increased and p62-positive staining is detected in neurons, including potential axonal beadings, as well as in the vasculature and in corpora amylacea. Interestingly, p62 is also increased in the neurons in 12-month-old
mice. In brain homogenates from 12-month-old
mice, both p62 and light chain 3 (LC3)-II levels are increased as compared to wildtype (WT) mice, indicating inhibited autophagy. Double immunostaining for LC3 and Aβ revealed LC3-positive puncta in hippocampus of 24-month-old
mice around the Aβ plaques which was subsequently identified by electron microscopy imaging as an accumulation of autophagic vacuoles in dystrophic neurites around the Aβ plaques. Taken together, autophagy is impaired in
knock-in mice upon increased Aβ pathology, indicating that
knock-in mouse models provide a platform for understanding the correlation between Aβ and autophagy.
Abstract
Background
Delirium is common in older hospitalized patients. It has serious consequences e.g., poor health outcomes, mortality and increased costs. Despite that, many cases are undetected. ...Early detection of delirium is important in improving outcomes and use of assessment tools improves detection rates. The 4AT is a brief screening tool for delirium detection, which has not previously been translated into Swedish. The study aim was to evaluate diagnostic accuracy and clinical applicability of a Swedish version of the screening tool 4AT for delirium detection.
Method
This diagnostic test accuracy study used a quantitative and a qualitative approach and evaluated the patients’ and the health care professionals’ experiences of the tool. Study included 200 patients ≥65 years from a university hospital and a county hospital in two Swedish regions. Medical specialties were geriatric stroke/neurology, geriatric multimorbidity, severe cognitive impairment, orthopaedic, and urology. The translated 4AT was tested against the reference standard DSM-IV-TR criteria, based on the Organic Brain Syndrome scale and patient records. The 4AT was assessed simultaneously and independently by two assessors. Additionally, data was collected through patient record reviews, and questions about applicability to the patients (
n
= 200) and the assessors (
n
= 37). Statistical analyses, and qualitative content analyses were conducted.
Results
By reference standard 18% had delirium, and by 4AT 19%. The overall percent agreement was 88%, AUROC 0.808, sensitivity 0.70 (95% CI 0.51–0.84) and specificity 0.92 (95% CI 0.87–0.96). In the ward for severe cognitive impairment (
n
= 63) the 4AT was less sensitive and less specific. In the other wards (
n
= 132) sensitivity was 0.77 (95% CI 0.50–0.93), specificity 0.93 (95% CI 0.87–0.97), and AUROC 0.848. Interrater reliability (Kappa) was 0.918,
p
= < 0.001 (
n
= 144). The 4AT was well tolerated by patients, easy to use for health care professionals, and took a few minutes to conduct.
Conclusion
The Swedish version of 4AT is an accurate and applicable tool to use in clinical practice for detecting delirium in hospitalized patients across different medical specialities, and to use by different professionals and levels of seniority. To improve patient outcomes, we recommend the 4AT to be incorporated in clinical practice in health care settings in Sweden.
A possible involvement of the gene IL1RAP (interleukin-1 receptor-associated protein) in the pathogenesis of Alzheimer's disease (AD) has been suggested in GWASs of cerebrospinal fluid (CSF) tau ...levels and longitudinal change in brain amyloid burden. The aim of this study was to examine previously implicated genetic markers in and near IL1RAP in relation to AD risk, CSF tau and Aβ biomarkers, as well as cognitive decline, in a case (AD)-control study and an age homogenous population-based cohort. Genotyping of IL1RAP-related single nucleotide polymorphisms (SNPs), selected based on previous GWAS results, was performed. 3446 individuals (1154 AD cases and 2292 controls) were included in the analyses of AD risk, 1400 individuals (cognitively normal = 747, AD = 653) in the CSF biomarker analyses, and 861 individuals in the analyses of cognitive decline. We found no relation between IL1RAP-related SNPs and AD risk. However, CSF total-tau and phospho-tau were associated with the SNP rs9877502 (p = 6 × 10
and p = 5 × 10
). Further, nominal associations (p = 0.03-0.05) were found between three other SNPs and CSF biomarker levels, or levels of cognitive performance and decline in a sub-sample from the general population. These results support previous studies suggesting an association of IL1RAP with disease intensity of AD.
TOTAL CELL NUMBER IN FETAL BRAIN Samuelsen, Grethe Badsberg; Bogdanović, Nenad; Laursen, Henning ...
Image analysis & stereology,
05/2011, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Odprti dostop
In this study the material comprises brains from three aborted fetuses and two fullterm infants who died at birth.The gestational ages ranged from the 22nd week to term. All cases were without ...malformations, known chromosomal abnormality, hydrops, and systemic infections, and all had normal birth weights with fetal growth indices (observed birth weight/expected mean birth weight) between 0.9 - 1.05. The preliminary results show a five fold increase in the total cell population in the marginal zone/cortical plate, MZ/CP (future neocortex), from week 22 until term. In the transient subplate zone, SP, the total cell number was more than doubled from week 22 to week 30-35, and then decreased towards term. In the intermediate zone, IZ (future white matter), the total cell population was doubled from week 22 until term. The total cell number in the entricular/subventricular zone, VZ/SZ (germinal matrix), was reduced by a factor of five from week 22 until term. A histological differentiation between neurons and glial cells was not possible. The optical fractionator was used to estimate the total cell population in four characteristic developmental zones in the human fetal brain. Fetal brain tissue undergoes considerable and rather unpredictable shrinkage during fixation. However, using the fractionator principle it is possible to eliminate this problem, provided that the structure of interest (one brain hemisphere) is fully intact.
Abstract Introduction Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-β ...aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe , PS1 M146V , and PS1 EΔ9 mutations, 13 sporadic AD, and 14 control cases. Results3 H-PIB,3 H-florbetaben,3 H-AZD2184, and BTA-1 shared a high- and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The3 H-AZD2184 and3 H-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on3 H-AZD84 binding followed by3 H-florbetaben and minimal on3 H-PIB. Discussion This study implies amyloid tracers of different structures detect different sites on amyloid-β fibrils or conformations.
Novel insights on proteins involved in Alzheimer’s disease (AD) are needed. Since multiple cell types and matrix components are altered in AD, bulk analysis of brain tissue maybe difficult to ...interpret. In the current study, we isolated pyramidal cells from the cornu ammonis 1 (CA1) region of the hippocampus from five AD and five neurologically healthy donors using laser capture microdissection (LCM). The samples were analyzed by proteomics using
18
O-labeled internal standard and nano-high-performance liquid chromatography coupled to tandem mass spectrometry (HPLC-MS/MS) for relative quantification. Fold change between AD and control was calculated for the proteins that were identified in at least two individual proteomes from each group. From the 10 cases analyzed, 62 proteins were identified in at least two AD cases and two control cases. Creatine kinase B-type (CKB), 14-3-3-γ, and heat shock cognate 71 (Hsc71), which have not been extensively studied in the context of the human AD brain previously, were selected for further studies by immunohistochemistry (IHC). In hippocampus, semi-quantitative measures of IHC staining of the three proteins confirmed the findings from our proteomic analysis. Studies of the same proteins in the frontal cortex revealed that the alterations remained for CKB and 14-3-3-γ but not for Hsc71. Protein upregulation in CA1 neurons of final stage AD is either a result of detrimental, pathological effects, or from cell-specific protective response mechanisms in surviving neurons. Based on previous findings from experimental studies, CKB and Hsc71 likely exhibit protective effects, whereas 14-3-3-γ may represent a detrimental pathway. These new players could reflect pathways of importance for the development of new therapeutic strategies.
Dendrites and dendritic spine density regress extensively during aging in rats housed under standard conditions (SC), which can be ameliorated by housing in the enriched environment (EE). This event ...is particularly pronounced on neurons where high rates of plasticity are conceivable, such as on projection neurons of archicortical regions of dentate gyrus'. However, effects of EE on neocortical projection neurons are still poorly understood. Therefore, we investigated the effect of EE housing on a deep layer III (L3) and layer V pyramidal cell (L5) morphology in the associative occipital neocortex of male Sprague-Dawley rats at 24 months of age. Rats were randomly distributed in two groups and reared under either SC (n=5) or EE conditions (n=6) for 26 days. In depth quantitative analysis of dendritic tree morphology and spine density on occipital projection neurons, from Golgi-Cox stained sections, showed similar trend in both EE occipital layers L3 and L5. Significant increase was found in total number of dendritic segments (L3 - 37.5 %, L5 - 33 %) and in dendritic diameter of intermediate segments (for more than 20 %), while increase in total spine number was around the level of significance (p>0.55; L3 - 30 %, L5 - 64 %). These findings suggest an outgrowth of new dendritic segments, When compared to archicortical region of dentate gyrus, effects of aging in the associative occipital cortex were less pronounced. Taken together, these findings suggest that structures being more affected by the aging process are more susceptible to the environmental enrichment in old age.
Highlights • The number of DYT6 patients treated with GPi-DBS is still relatively small. • Most of the recent studies have shown moderate and less predictable improvement after GPi-DBS. • GPi-DBS ...outcome of DYT 6 could be excellent and promising. • The promising outcome may be related to some previously established predictors also found in our patient: (1) age < 20 years; (2) duration of dystonia < 15 years; and (3) absence of fixed skeletal deformities
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