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overview Alzheimer’s disease (AD), a prevalent, adult-onset, neurodegenerative disease, is clinically characterized by progressive impairments in cognition and memory. These clinical features are accompanied by characteristic histological changes in the brain, including neuronal loss, extracellular deposition of fibrillogenic Ab peptides in senile plaques and intracellular neurofibrillary tangles. The principal risk factors for AD are age and inheritance of mutant genes, or polymorphic alleles that predispose individuals to late-onset disease. Over the past 20 years, my laboratory has focused on examining the cellular and molecular biology of the b-amyloid precursor protein (APP), or presenilins (PS1 and PS2), molecules that are mutated in pedigrees with autosomal dominant, familial forms of Alzheimer's disease (FAD). The function(s) of APP in the central nervous system (CNS) are still not fully understood, but we have demonstrated that APP is subject to rapid anterograde axonal transport and subject to proteolytic processing at, or near, terminal fields. In collaboration with Robert Malinow at UCSD, we have also shown that synaptic activity modulates APP processing and Ab production, and that both axonal and dendritic release of these peptides alter spine dynamics and glutamatergic neurotransmission. Our current efforts are focused on clarifying the dynamics and regulation of APP trafficking and processing cultured neurons and hippocampal slices using recombinant lentiviral-driven APP-GFP chimeras and live cell imaging approaches. In order to assess the normal function of PS, we have used gene targeting strategies; PS1-deficient animals die in late embryogenesis due to defective Notch signaling that is in large part, the result of failed intramembranous, “g-secretase” processing of a membrane-bound Notch substrates. This “g-secretase” activity is also responsible for liberating Ab peptides from membrane-bound APP derivatives. We, and others, have provided genetic and biochemical evidence has revealed that PS associates with nicastrin (NCT), APH-1 and PEN-2 in high molecular weight complexes, and our current efforts are aimed at understanding the temporal assembly of these membrane proteins, the nature of subunit interactions and the enzymatic mechanism(s) by which the complex promotes “g-secretase” processing of Notch, APP and other type 1 membrane proteins. A significant effort of our laboratory has been to develop and characterize transgenic animals that express FAD-linked variants of PS1 and APP to clarify the underlying biochemical and pathophysiological alterations that cause AD. We have exploited these animals, as well as animals in which we have conditionally inactivated PS, to clarify issues relevant to axonal trafficking of membrane proteins, neurodegeneration, neuronal vulnerability, gene expression and APP/Ab metabolism. A significant effort in our laboratory is focused on understanding the cell non-autonomous effects of FAD-linked mutant PS1 expression on hippocampal neurogenesis. Our future studies will focus heavily on the mechanisms that are responsible for the observed effects using temporal and system-specific conditional gene inactivation approaches. Extending our demonstration that enriched environments and exercise modulates Ab metabolism and deposition in vivo, our ongoing efforts are focused on the role of polypeptides encoded by genes that are selectively regulated in these settings. Finally, we have been exploring the impact of the microbiome in modulation of amyloid deposition in mouse models of AD. In summary, my research program is designed to integrate genetic, neurobiologic, molecular and cellular information to clarify the normal biology of APP and PS and the mechanisms by which mutant genes cause AD. The value of animal models that recapitulate some features of the human disease have, and will be of enormous value for addressing issues relevant to the selective vulnerability of specific CNS systems, the pathophysiological sequelae and ultimately, will provide opportunities to explore mechanism-based therapeutic strategies.

One or more keywords matched the following items that are connected to Sisodia, Sangram S.

Item TypeName
Concept Disease Models, Animal
Academic Article Novel neuritic clusters with accumulations of amyloid precursor protein and amyloid precursor-like protein 2 immunoreactivity in brain regions damaged by thiamine deficiency.
Academic Article Loss of functional prion protein: a role in prion disorders?
Academic Article Neuronal degeneration in human diseases and animal models.
Academic Article Motor neuron disease and model systems: aetiologies, mechanisms and therapies.
Academic Article Amyloidosis in aging and Alzheimer's disease.
Academic Article Amyloidogenesis in Alzheimer's disease: basic biology and animal models.
Academic Article Alzheimer's disease: genetic studies and transgenic models.
Academic Article ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.
Academic Article Toxicity of synthetic A beta peptides and modeling of Alzheimer's disease.
Academic Article Genetic neurodegenerative diseases: the human illness and transgenic models.
Academic Article Amyotrophic lateral sclerosis and Alzheimer disease. Lessons from model systems.
Academic Article The value of transgenic models for the study of neurodegenerative diseases.
Academic Article Aged non-human primates: an animal model of age-associated neurodegenerative disease.
Academic Article Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice.
Academic Article Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice.
Academic Article Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1DeltaE9 transgenic mice.
Academic Article Adult neurogenesis is functionally associated with AD-like neurodegeneration.
Academic Article Neuronal responses to injury and aging: lessons from animal models.
Academic Article Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin).
Academic Article Amyloid-related proteins and nerve growth factor in Alzheimer's disease and animal models.
Academic Article P75 neurotrophin receptor regulates expression of neural cell adhesion molecule 1.
Academic Article Abeta star: a light onto synaptic dysfunction?
Academic Article Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease.
Academic Article Cellular and molecular biology of Alzheimer's disease and animal models.
Academic Article Neuronal disorders: studies of animal models and human diseases.
Academic Article Cellular and molecular biology of Alzheimer's disease and animal models.
Academic Article A mouse model for Down syndrome exhibits learning and behaviour deficits.
Academic Article Alzheimer's disease-type brain abnormalities in animal models.
Academic Article Plug-based microfluidics with defined surface chemistry to miniaturize and control aggregation of amyloidogenic peptides.
Academic Article Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease.
Academic Article Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1?E9 murine model of Alzheimer's disease.
Academic Article Sex-specific effects of microbiome perturbations on cerebral Aß amyloidosis and microglia phenotypes.
Academic Article An APP ectodomain mutation outside of the Aß domain promotes Aß production in vitro and deposition in vivo.

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