Project description:We describe in vivo follow-up PET imaging and postmortem findings from an autosomal dominant Alzheimer’s disease (ADAD) PSEN1 E280A carrier who was also homozygous for the APOE3 Christchurch (APOE3ch) variant and was protected against Alzheimer’s symptoms for almost three decades beyond the expected age of onset. We identified a distinct anatomical pattern of tau pathology with atypical accumulation in vivo and unusual postmortem regional distribution characterized by sparing in the frontal cortex and severe pathology in the occipital cortex. The frontal cortex and the hippocampus, less affected than the occipital cortex by tau pathology, contained Related Orphan Receptor B (RORB) positive neurons, homeostatic astrocytes and higher APOE expression. The occipital cortex, the only cortical region showing cerebral amyloid angiopathy (CAA), exhibited a distinctive chronic inflammatory microglial profile and lower APOE expression. Thus, the Christchurch variant impacts the distribution of tau pathology, modulates age at onset, severity, progression, and clinical presentation of ADAD, suggesting possible therapeutic strategies.
Project description:Autosomal dominant tubulointerstitial kidney disease (ADTKD) caused by UMOD mutations is characterized by strong interfamilial variability. We generated two mutant Umod knock-in mouse models, harbouring two mutations associated with drastic differences in kidney survival in ADTKD patients. We performed bulk RNA-sequencing of kidney extracts from Umod KI mice at an early (1 month) and advanced (4 months) stage of disease.
Project description:Background: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Methods: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Results: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways. Conclusions: Autosomal dominant polycystic kidney disease (ADPKD) affects more than 12 million people worldwide. Mutations in PKD1 and PKD2 cause cyst formation through unknown mechanisms. To unravel the pathogenic mechanisms in ADPKD, multiple studies have investigated transcriptional mis-regulation in cystic kidneys from patients and mouse models, and numerous dysregulated genes and pathways have been described. Yet, the concordance between studies has been rather limited. Furthermore, the cellular and genetic diversity in cystic kidneys has hampered the identification of mis-expressed genes in kidney epithelial cells with homozygous PKD mutations, which are critical to identify polycystin-dependent pathways.
Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients.
Project description:The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. Understanding cell type specificity and local spatial contributions to different AD etiologies is instrumental to optimize therapeutic strategies for precision medicine. In this study, we compared cell-specific transcriptomes from the frontal cortex of carriers with the autosomal dominant mutation, PSEN1-E280A, sporadic AD and controls. Among the pathways that distinguished the autosomal dominant AD mutation disease from sporadic AD was increased autophagy and proteostasis pathways in astrocytes and oligodendrocytes in the former. Synaptic genes associated with neurofibrillary tangles in excitatory neurons were increased in both sporadic AD and mutation carriers. Spatial transcriptomics in samples from frontal cortex and CA1 hippocampus in PSEN1-E280A cases compared to non-diseased control individuals further validated the activation of chaperone-mediated autophagy genes and NFT-associated genes in E280A cases compared to controls. In conclusion, although autosomal dominant Alzheimer’s disease (ADAD) and sporadic AD share many features, the uniqueness of the cellular responses in each condition must be taken into consideration when designing clinical studies and therapeutics.
Project description:The heterogeneous etiology of Alzheimer’s disease (AD) challenges therapeutic development. Understanding cell type gene expression specificity and local spatial contributions to different AD etiologies is instrumental to optimize therapeutic strategies for precision medicine. In this study, we compared cell-specific transcriptomes from the frontal cortex of carriers with the autosomal dominant mutation, PSEN1-E280A, Sporadic AD and Controls. Among the pathways that distinguished the autosomal dominant AD mutation disease from sporadic AD was increased autophagy and proteostasis pathways in astrocytes and oligodendrocytes in the former. Synaptic genes associated with neurofibrillary tangles in excitatory neurons were increased in both sporadic AD and mutation carriers. Spatial transcriptomics in samples from frontal cortex and CA1 hippocampus in PSEN1-E280A cases compared to non-diseased control individuals further validated the activation of chaperone-mediated autophagy genes and NFT-associated genes in E280A cases compared to controls. In conclusion, although autosomal dominant Alzheimer’s disease (ADAD) and sporadic AD share many features, the uniqueness of the cellular responses in each condition must be taken into consideration when designing clinical studies and therapeutics.