93 research outputs found
A Novel Mouse Model of Alzheimer's Disease with Chronic Estrogen Deficiency Leads to Glial Cell Activation and Hypertrophy
The role of estrogens in Alzheimer's disease (AD) involving β-amyloid (Aβ) generation and plaque formation was mostly tested in ovariectomized mice with or without APP mutations. The aim of the present study was to explore the abnormalities of neural cells in a novel mouse model of AD with chronic estrogen deficiency. These chimeric mice exhibit a total FSH-R knockout (FORKO) and carry two transgenes, one expressing the β-amyloid precursor protein (APPsw, Swedish mutation) and the other expressing presenilin-1 lacking exon 9 (PS1Δ9). The most prominent changes in the cerebral cortex and hippocampus of these hypoestrogenic mice were marked hypertrophy of both cortical neurons and astrocytes and an increased number of activated microglia. There were no significant differences in the number of Aβ plaques although they appeared less compacted and larger than those in APPsw/PS1Δ9 control mice. Similar glia abnormalities were obtained in wild-type primary cortical neural cultures treated with letrozole, an aromatase inhibitor. The concordance of results from APPsw/PS1Δ9 mice with or without FSH-R deletion and those with letrozole treatment in vitro (with and without Aβ treatment) of primary cortical/hippocampal cultures suggests the usefulness of these models to explore molecular mechanisms involved in microglia and astrocyte activation in hypoestrogenic states in the central nervous system
Short-range correlations in two-nucleon knockout reactions
A theory of short-range correlations in two-nucleon removal due to elastic
breakup (diffraction dissociation) on a light target is developed. Fingerprints
of these correlations will appear in momentum distributions of back-to-back
emission of the nucleon pair. Expressions for the momentum distributions are
derived and calculations for reactions involving stable and unstable nuclear
species are performed. The signature of short-range correlations in other
reaction processes is also studied.Comment: Nuclear Physics A, in pres
Pullulan-based nanoparticles as carriers for transmucosal protein delivery
Polymeric nanoparticles have revealed very effective in transmucosal delivery of
proteins. Polysaccharides are among the most used materials for the production of these
carriers, owing to their structural flexibility and propensity to evidence biocompatibility
and biodegradability. In parallel, there is a preference for the use of mild methods for
their production, in order to prevent protein degradation, ensure lower costs and easier
procedures that enable scaling up.
In this work we propose the production of pullulan-based nanoparticles by a mild
method of polyelectrolyte complexation. As pullulan is a neutral polysaccharide,
sulfated and aminated derivatives of the polymer were synthesized to provide pullulan
with a charge. These derivatives were then complexed with chitosan and carrageenan,
respectively, to produce the nanocarriers. Positively charged nanoparticles of 180-270
nm were obtained, evidencing ability to associate bovine serum albumin, which was
selected as model protein. In PBS pH 7.4, pullulan-based nanoparticles were found to
have a burst release of 30% of the protein, which maintained up to 24h. Nanoparticle
size and zeta potential were preserved upon freeze-drying in the presence of appropriate
cryoprotectants. A factorial design was approached to assess the cytotoxicity of raw
materials and nanoparticles by the metabolic test MTT. Nanoparticles demonstrated to
not cause overt toxicity in a respiratory cell model (Calu-3). Pullulan has, thus,
demonstrated to hold potential for the production of nanoparticles with an application in
protein delivery
Multiple scattering effects in proton nucleus elastic scattering at intermediate energies
Nanochaperone‐Based Strategies to Control Protein Aggregation Linked to Conformational Diseases
Letrozole Potentiates Mitochondrial and Dendritic Spine Impairments Induced by β Amyloid
Reduced estrogens, either through aging or postsurgery breast cancer treatment with the oral nonsteroidal aromatase inhibitor letrozole, are linked with declined cognitive abilities. However, a direct link between letrozole and neuronal deficits induced by pathogenic insults associated with aging such as beta amyloid (Aβ1–42) has not been established. The objective of this study was to determine if letrozole aggravates synaptic deficits concurrent with Aβ1–42 insult. We examined the effects of letrozole and oligomeric Aβ1–42 treatment in dissociated and organotypic hippocampal slice cultures. Changes in glial cell morphology, neuronal mitochondria, and synaptic structures upon letrozole treatment were monitored by confocal microscopy, as they were shown to be affected by Aβ1–42 oligomers. Oligomeric Aβ1–42 or letrozole alone caused decreases in mitochondrial volume, dendritic spine density, synaptophysin (synaptic marker), and the postsynaptic protein, synaptopodin. Here, we demonstrated that mitochondrial and synaptic structural deficits were exacerbated when letrozole therapy was combined with Aβ1–42 treatment. Our novel findings suggest that letrozole may increase neuronal susceptibility to pathological insults, such as oligomeric Aβ1–42 in Alzheimer’s disease (AD). These changes in dendritic spine number, synaptic protein expression, and mitochondrial morphology may, in part, explain the increased prevalence of cognitive decline associated with aromatase inhibitor use
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