Project description:In the present study we addressed several questions related to the mechanisms of cortical injury. We analyzed genome wide gene expression by microarrays, comparing active multiple sclerosis lesions with highly inflammatory lesions of chronic tuberculous meningitis, with neurodegenerative lesions of Alzheimer’s disease and with normal cortex of age matched controls.
Project description:In the present study we addressed several questions related to the mechanisms of cortical injury. We analyzed genome wide gene expression by microarrays, comparing active multiple sclerosis lesions with highly inflammatory lesions of chronic tuberculous meningitis, with neurodegenerative lesions of Alzheimer’s disease and with normal cortex of age matched controls. To clarify which inflammatory mediators drive demyelination in the human cortex, we characterized and compared the gene expression profile of cortices derived from patients with progressive Multiple Sclerosis (pMS), Meningitis tuberculosis (MT), Alzheimers disease (AD) as well as of normal cortex from age matched controls. 3 cases of each disease were included into the study. Preceding the gene expression profiling all cases were characterized histologically and areas of interest were identified. RNA was isolated from those areas, amplified and hybridized to Agilent G4112F whole genome microarrays.
Project description:The pathological basis of multiple sclerosis involves damage to both myelin sheaths and axons. Demyelination and axonal transection are considered to cause reversible and irreversible neurological deficits respectively, gradually destroying the neuronal circuitry of the CNS. In order to analyse the individual effects of the pathological hallmarks of multiple sclerosis on neurons, the pontocerebellar pathway was targeted with either lysolecithin-induced chemical demyelination or complete pathway transection. Transcriptional changes in the pontocerebellar neuronal nuclei were investigated with microarrays at days 4, 10 and 37 post-intervention to identify underlying molecular responses. A common as well as unique set of injury response genes was identified in the transection and the demyelination conditions. The increased expression of activating transcription factor 3 (Atf3) and thyrotropin-releasing hormone (Trh) in both injury paradigms was validated by immunohistochemistry. Expression of Atf3 in a patient with Marburg’s variant of multiple sclerosis was also detected in the pons with large cerebellar demyelination, confirming the activation of the Atf3 pathway in a human disease sample as well. This experimental approach may be useful for the identification of pathways that could be targeted for remyelinative and neuroprotective drug development.
Project description:Diverse immune cells move from the calvaria marrow into the dura mater via recently discovered skull-meninges connections (SMCs). Yet, how the calvaria bone marrow is different from the other bones and whether it plays a special role in human diseases remain unknown. Using multi-omics approaches and whole mouse transparency we reveal that bone marrow cells are highly heterogeneous across the mouse body. The calvaria harbors the most distinct molecular signature with hundreds of differentially expressed genes and proteins. Acute brain injury induces skull-specific outcomes including increased calvaria cell numbers. Moreover, TSPO-PET imaging of stroke, dementia and multiple sclerosis patients demonstrate increased inflammation in the human skull, mirroring the underlying brain inflammation.
Project description:Cortical tubers in patients with tuberous sclerosis complex (TSC) are associated with cognitive disability and intractable epilepsy. While these developmental malformations are believed to result from the effects of TSC1 or TSC2 Gene mutations, the molecular mechanisms leading to tuber formation during brain development as well as the onset of seizures remain largely unknown. We used the Affymetrix Gene Chip platform as a genome-wide strategy to define the Gene expression profile of cortical tubers resected during epilepsy surgery compared to histologically normal perituberal tissue (adjacent to the cortical tuber) from the same patients or autopsy control tissue.