ABSTRACT
Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the Western world and is characterized by a progressive loss of cognitive functions leading to dementia. One major histopathological hallmark of AD is the formation of amyloid-beta plaques, which is reproduced in numerous transgenic animal models overexpressing pathogenic forms of amyloid precursor protein (APP). In human AD and in transgenic amyloid plaque mouse models, several studies report altered rates of adult neurogenesis, i.e. the formation of new neurons from neural stem and progenitor cells, and impaired neurogenesis has also been attributed to contribute to the cognitive decline in AD. So far, changes in neurogenesis have largely been considered to be a consequence of the plaque pathology. Therefore, possible alterations in neurogenesis before plaque formation or in prodromal AD have been largely ignored. Here, we analysed adult hippocampal neurogenesis in amyloidogenic mouse models of AD at different points before and during plaque progression. We found prominent alterations of hippocampal neurogenesis before plaque formation. Survival of newly generated cells and the production of new neurons were already compromised at this stage. Moreover and surprisingly, proliferation of doublecortin (DCX) expressing neuroblasts was significantly and specifically elevated during the pre-plaque stage in the APP-PS1 model, while the Nestin-expressing stem cell population was unaffected. In summary, changes in neurogenesis are evident already before plaque deposition and might contribute to well-known early hippocampal dysfunctions in prodromal AD such as hippocampal overactivity.
Subject(s)
Alzheimer Disease/pathology , Hippocampus/pathology , Neurogenesis , Alzheimer Disease/metabolism , Animals , Cell Count , Cell Lineage , Cell Proliferation , Cell Survival , Dentate Gyrus/pathology , Disease Models, Animal , Doublecortin Domain Proteins , Doublecortin Protein , Female , Mice, Transgenic , Microtubule-Associated Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Neuropeptides/metabolism , Plaque, Amyloid/metabolism , Plaque, Amyloid/pathologyABSTRACT
The corpus callosum is the largest commissural fiber connecting left and right hemisphere of the brain. Emerging evidence suggests that a variety of abnormalities detected in the microstructure of this white matter fiber can be an early event in Alzheimer's disease (AD) pathology. However, little is known about tissue characteristics of these abnormalities and how these abnormalities evolve during AD progression. In this study, we measured in vivo magnetic resonance transverse relaxation times (T2) to longitudinally monitor changes in tissue integrity and abnormalities related to myelination and demyelination processes in corpus callosum of AD mouse models. The most striking finding of our study was a significant elongation of T2 values in the corpus callosum at 10, 14, 16 and 18 months of age compared to age-matched wild-type mice. In contrast, the gray matter regions surrounding the corpus callosum, such as the cortex and hippocampus, showed a significant T2 decrease compared to wild-type mice. Histological analyses clearly revealed demyelination, gliosis and amyloid-plaque deposition in the corpus callosum. Our results suggest that demyelinating and inflammatory pathology may result in prolonged relaxation time during AD progression. To our knowledge, this is the first in vivo T2 study assessing the microstructural changes with age in the corpus callosum of the Tg2576 mouse model and it demonstrates the application of T2 measurement to noninvasively detect tissue integrity of the corpus callosum, which can be an early event in disease progression.
Subject(s)
Alzheimer Disease/pathology , Corpus Callosum/pathology , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Astrocytes/pathology , Cerebral Cortex/pathology , Cerebral Cortex/physiopathology , Corpus Callosum/physiopathology , Demyelinating Diseases/pathology , Demyelinating Diseases/physiopathology , Disease Models, Animal , Disease Progression , Female , Fluorescent Antibody Technique , Hippocampus/pathology , Hippocampus/physiopathology , Longitudinal Studies , Magnetic Resonance Imaging , Male , Mice, Inbred C57BL , Mice, Transgenic , Thalamus/pathology , Thalamus/physiopathologySubject(s)
Biomarkers, Tumor/genetics , Gene Expression Profiling , Prostatic Neoplasms/genetics , Transcription Factors/genetics , Biopsy , Humans , Male , Prognosis , Prostate/pathology , Prostate-Specific Antigen/blood , Prostatic Neoplasms/diagnosis , Prostatic Neoplasms/pathology , Sensitivity and SpecificitySubject(s)
Carcinoma, Renal Cell/secondary , Gene Expression Profiling , Kidney Neoplasms/genetics , Lung Neoplasms/secondary , Carcinoma, Renal Cell/genetics , Carcinoma, Renal Cell/pathology , Carcinoma, Renal Cell/surgery , DNA, Neoplasm/genetics , Gene Expression Regulation, Neoplastic/physiology , Humans , Kidney Neoplasms/pathology , Kidney Neoplasms/surgery , Laser Therapy , Lung/pathology , Lung/surgery , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Lung Neoplasms/surgery , Oligonucleotide Array Sequence Analysis , Polymorphism, Single Nucleotide/genetics , PrognosisABSTRACT
SETTING: Four hundred and sixty-eight isoniazid (INH) resistant Mycobacterium tuberculosis isolates recovered from a selected Brazilian population. OBJECTIVE: To check for susceptibility to other chemotherapeutic drugs used in TB treatment, and to ascertain mutations involved in INH and rifampicin (RMP) resistance. DESIGN: Antimicrobial susceptibility to RMP, streptomycin and ethambutol (EMB) was evaluated by the resistance ratio method and pyrazinamide (PZA) by activity assay. Single strand conformation polymorphism (SSCP) and sequence analysis were performed in samples from this panel to confirm mutations in codon 315 of the katG and in a 69-bp region of the rpoB gene. RESULTS: Combined resistance to INH+RMP, INH+ PZA, INH+EMB, and INH+RMP+PZA was shown in respectively 272 (58.1%), 126 (26.9%), 47 (10%), 116 (24.8%) isolates. No katG mutation was found in 19 (39.6%) of 48 strains tested. Ser315Thr substitution was found in 29 (60.4%). All RMP-resistant strains tested (n = 25) showed rpoB mutations. S531L substitution was found in 15 (60%). CONCLUSION: INH-resistant strains isolated from selected Brazilian populations frequently show resistance to other first-line anti-tuberculosis drugs. rpoB mutation was responsible for RMP resistance in all strains. Among INHr strains, katG mutations were shown in only 60.4%. Genetic approaches targeting the rpoB gene but not the katG gene have a high sensitivity to detect resistance among Brazilian M. tuberculosis strains.
