56 research outputs found
PLA2 G4E, a candidate gene for resilience in Alzheimer's disease and a new target for dementia treatment
Clinical studies revealed that some aged-individuals accumulate a significant number of histopathological Alzheimer´s disease (AD) lesions in their brain, yet without developing any signs of dementia. Animal models of AD represent suitable tools to identify genes that might promote cognitive resilience and hence, this study first set out to identify cognitively resilient individuals in the aged-Tg2576 mouse model. A transcriptomic analysis of these mice identified PLA2 G4E as a gene that might confer resistance to dementia. Indeed, a significant decrease in PLA2 G4E is evident in the brain of late-stage AD patients, whereas no such changes are observed in early stage patients with AD neuropathological lesions but no signs of dementia. We demonstrated that adeno-associated viral vector-mediated overexpression of PLA2 G4E in hippocampal neurons completely restored cognitive deficits in elderly APP/PS1 mice, without affecting the amyloid or tau pathology. These PLA2 G4E overexpressing APP/PS1 mice developed significantly more dendritic spines than sham-injected mice, coinciding with the cognitive improvement observed. Hence, these results support the idea that a loss of PLA2 G4E might play a key role in the onset of dementia in AD, highlighting the potential of PLA2 G4E overexpression as a novel therapeutic strategy to manage AD and other disorders that course with memory deficits
Glucocerebrosidase expression patterns in the non-human primate brain
Glucocerebrosidase (GCase) is a lysosomal
enzyme encoded by the GBA1 gene. Mutations in GBA1
gene lead to Gaucher’s disease, the most prevalent lysosomal storage disorder. GBA1 mutations reduce GCase
activity, therefore promoting the aggregation of alphasynuclein, a common neuropathological finding underlying
Parkinson’s disease (PD) and dementia with Lewy bodies.
However, it is also worth noting that a direct link between
GBA1 mutations and alpha-synuclein aggregation indicating cause and effect is still lacking, with limited experimental evidence to date. Bearing in mind that a number of
strategies increasing GCase expression for the treatment of
PD are currently under development, here we sought to
analyze the baseline expression of GCase in the brain of
Macaca fascicularis, which has often been considered as
the gold-standard animal model of PD. Although as with
other lysosomal enzymes, GCase is expected to be ubiquitously expressed, here a number of regional variations
have been consistently found, together with several specific
neurochemical phenotypes expressing very high levels of
GCase. In this regard, the most enriched expression of
GCase was constantly found in cholinergic neurons from
the nucleus basalis of Meynert, dopaminergic cells in the
substantia nigra pars compacta, serotoninergic neurons
from the raphe nuclei, as well as in noradrenergic neurons
located in the locus ceruleus. Moreover, it is also worth
noting that moderate levels of expression were also found
in a number of areas within the paleocortex and archicortex, such as the entorhinal cortex and the hippocampal
formation, respectively
Calbindin content and differential vulnerability of midbrain efferent dopaminergic neurons in macaques
Calbindin (CB) is a calcium binding protein reported to protect dopaminergic neurons from
degeneration. Although a direct link between CB content and differential vulnerability of
dopaminergic neurons has long been accepted, factors other than CB have also been
suggested, particularly those related to the dopamine transporter. Indeed, several studies
have reported that CB levels are not causally related to the differential vulnerability
of dopaminergic neurons against neurotoxins. Here we have used dual stains for
tyrosine hydroxylase (TH) and CB in 3 control and 3 MPTP-treated monkeys to visualize
dopaminergic neurons in the ventral tegmental area (VTA) and in the dorsal and ventral
tiers of the substantia nigra pars compacta (SNcd and SNcv) co-expressing TH and CB.
In control animals, the highest percentages of co-localization were found in VTA (58.2%),
followed by neurons located in the SNcd (34.7%). As expected, SNcv neurons lacked CB
expression. In MPTP-treated animals, the percentage of CB-ir/TH-ir neurons in the VTA
was similar to control monkeys (62.1%), whereas most of the few surviving neurons in
the SNcd were CB-ir/TH-ir (88.6%). Next, we have elucidated the presence of CB within
identified nigrostriatal and nigroextrastriatal midbrain dopaminergic projection neurons. For
this purpose, two control monkeys received one injection of Fluoro-Gold into the caudate
nucleus and one injection of cholera toxin (CTB) into the postcommissural putamen,
whereas two more monkeys were injected with CTB into the internal division of the globus
pallidus (GPi). As expected, all the nigrocaudate- and nigroputamen-projecting neurons
were TH-ir, although surprisingly, all of these nigrostriatal-projecting neurons were negative
for CB. Furthermore, all the nigropallidal-projecting neurons co-expressed both TH and
CB. In summary, although CB-ir dopaminergic neurons seem to be less prone to MPTPinduced
degeneration, our data clearly demonstrated that these neurons are not giving rise
to nigrostriatal projections and indeed CB-ir/TH-ir neurons only originate nigroextrastriatal
projections
Adverse anthropometric risk profile in biochemically controlled acromegalic patients: comparison with an age- and gender-matched primary care population
GH and IGF-1 play an important role in the regulation of metabolism and body composition. In patients with uncontrolled acromegaly, cardiovascular morbidity and mortality are increased but are supposed to be normalised after biochemical control is achieved. We aimed at comparing body composition and the cardiovascular risk profile in patients with controlled acromegaly and controls. A cross-sectional study. We evaluated anthropometric parameters (height, weight, body mass index (BMI), waist and hip circumference, waist to height ratio) and, additionally, cardiovascular risk biomarkers (fasting plasma glucose, HbA1c, triglycerides, total cholesterol, HDL, LDL, and lipoprotein (a), in 81 acromegalic patients (58% cured) compared to 320 age- and gender-matched controls (ratio 1:4), sampled from the primary care patient cohort DETECT. The whole group of 81 acromegalic patients presented with significantly higher anthropometric parameters, such as weight, BMI, waist and hip circumference, but with more favourable cardiovascular risk biomarkers, such as fasting plasma glucose, total cholesterol, triglycerides and HDL levels, in comparison to their respective controls. Biochemically controlled acromegalic patients again showed significantly higher measurements of obesity, mainly visceral adiposity, than age- and gender-matched control patients (BMI 29.5 ± 5.9 vs. 27.3 ± 5.8 kg/m2; P = 0.020; waist circumference 100.9 ± 16.8 vs. 94.8 ± 15.5 cm; P = 0.031; hip circumference 110.7 ± 9.9 vs. 105.0 ± 11.7 cm; P = 0.001). No differences in the classical cardiovascular biomarkers were detected except for fasting plasma glucose and triglycerides. This effect could not be attributed to a higher prevalence of type 2 diabetes mellitus in the acromegalic patient group, since stratified analyses between the subgroup of patients with acromegaly and controls, both with type 2 diabetes mellitus, revealed that there were no significant differences in the anthropometric measurements. Biochemically cured acromegalic patients pertain an adverse anthropometric risk profile, mainly because of elevated adiposity measurements, such as BMI, waist and hip circumference, compared to an age- and gender-matched primary care population
Adeno-associated viral vectors serotype 8 for cell-specific delivery of therapeutic genes in the central nervous system
Adeno-associated viruses (AAVs) have become highly promising tools for research and clinical applications in the central nervous system (CNS). However, specific delivery of genes to the cell type of interest is essential for the success of gene therapy and therefore a correct selection of the promoter plays a very important role. Here, AAV8 vectors carrying enhanced green fluorescent protein (eGFP) as reporter gene under the transcriptional control of different CNS-specific promoters were used and compared with a strong ubiquitous promoter. Since one of the main limitations of AAV-mediated gene delivery lies in its restricted cloning capacity, we focused our work on small-sized promoters. We tested the transduction efficacy and specificity of each vector after stereotactic injection into the mouse striatum. Three glia-specific AAV vectors were generated using two truncated forms of the human promoter for glial fibrillar acidic protein (GFAP) as well as a truncated form of the murine GFAP promoter. All three vectors resulted in predominantly glial expression; however we also observed eGFP expression in other cell-types such as oligodendrocytes, but never in neurons. In addition, robust and neuron-specific eGFP expression was observed using the minimal promoters for the neural protein BM88 and the neuronal nicotinic receptor β2 (CHRNB2). In summary, we developed a set of AAV vectors designed for specific expression in cells of the CNS using minimal promoters to drive gene expression when the size of the therapeutic gene matters
Effects of Once-Weekly Exenatide on Cardiovascular Outcomes in Type 2 Diabetes.
Abstract
BACKGROUND:
The cardiovascular effects of adding once-weekly treatment with exenatide to usual care in patients with type 2 diabetes are unknown.
METHODS:
We randomly assigned patients with type 2 diabetes, with or without previous cardiovascular disease, to receive subcutaneous injections of extended-release exenatide at a dose of 2 mg or matching placebo once weekly. The primary composite outcome was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The coprimary hypotheses were that exenatide, administered once weekly, would be noninferior to placebo with respect to safety and superior to placebo with respect to efficacy.
RESULTS:
In all, 14,752 patients (of whom 10,782 [73.1%] had previous cardiovascular disease) were followed for a median of 3.2 years (interquartile range, 2.2 to 4.4). A primary composite outcome event occurred in 839 of 7356 patients (11.4%; 3.7 events per 100 person-years) in the exenatide group and in 905 of 7396 patients (12.2%; 4.0 events per 100 person-years) in the placebo group (hazard ratio, 0.91; 95% confidence interval [CI], 0.83 to 1.00), with the intention-to-treat analysis indicating that exenatide, administered once weekly, was noninferior to placebo with respect to safety (P<0.001 for noninferiority) but was not superior to placebo with respect to efficacy (P=0.06 for superiority). The rates of death from cardiovascular causes, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, hospitalization for heart failure, and hospitalization for acute coronary syndrome, and the incidence of acute pancreatitis, pancreatic cancer, medullary thyroid carcinoma, and serious adverse events did not differ significantly between the two groups.
CONCLUSIONS:
Among patients with type 2 diabetes with or without previous cardiovascular disease, the incidence of major adverse cardiovascular events did not differ significantly between patients who received exenatide and those who received placebo. (Funded by Amylin Pharmaceuticals; EXSCEL ClinicalTrials.gov number, NCT01144338 .)
Glucocerebrosidase gene therapy in animal models of Parkinson Disease
Parkinson´s Disease (PD) is the first most common movement disorder and second most common neurodegenerative disease that affects 1.5% of the global population above 65 years old. Although the incidence of PD varies depending on genetic, race/ethnicity and environmental factors, advanced age has been appointed as the main risk factor for PD
An alternative approach to (S)- and (R)-2-methylglycidol O-benzyl ether derivatives
This report describes the gram scale synthesis of (S)- and (R)-2,2,4-trimethyl-4-(hydroxymethyl)-1,3-dioxolanes using the Sharpless asymmetric dihydroxylation (AD) of the Weinreb amide of 2-methyl-2-propenoic acid. The 2-methylglycerol acetonides resultant from protection of the AD products were used as starting materials in the synthesis of O-benzyl ethers of the valuable C4-chiral building blocks (S)- and (R)-2-methylglycidol. © 2001 Elsevier Science Ltd
A straightforward synthesis of both enantiomers of alfa-vinylalanine and alfa-ethynylalanine
This report describes the synthesis of enantiomerically pure (S)- and (R)--vinylalanines and (S)- and (R)--ethynylalanines, four quaternary - amino acids, using a straightforward synthetic route and starting from (S)- and (R)-N-Boc-N,O-isopropylidene--methylserinals. (C) 1999 Elsevier Science Ltd
Glucocerebrosidase gene therapy in animal models of Parkinson Disease
Parkinson´s Disease (PD) is the first most common movement disorder and second most common neurodegenerative disease that affects 1.5% of the global population above 65 years old. Although the incidence of PD varies depending on genetic, race/ethnicity and environmental factors, advanced age has been appointed as the main risk factor for PD
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