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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

Item TypeName
Concept Membrane Proteins
Academic Article Endoproteolysis of presenilin 1 and accumulation of processed derivatives in vivo.
Academic Article Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
Academic Article Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling.
Academic Article A vector for expressing foreign genes in the brains and hearts of transgenic mice.
Academic Article Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.
Academic Article Presenilin 1 facilitates the constitutive turnover of beta-catenin: differential activity of Alzheimer's disease-linked PS1 mutants in the beta-catenin-signaling pathway.
Academic Article Alzheimer's disease: genetic studies and transgenic models.
Academic Article An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos.
Academic Article Lack of requirement for presenilin1 in Notch1 signaling.
Academic Article Endoproteolytic processing and stabilization of wild-type and mutant presenilin.
Academic Article Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.
Academic Article Effects of PS1 deficiency on membrane protein trafficking in neurons.
Academic Article Beta-amyloid precursor protein cleavage by a membrane-bound protease.
Academic Article Furin mediates enhanced production of fibrillogenic ABri peptides in familial British dementia.
Academic Article Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1.
Academic Article Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
Academic Article Processing of presenilin 1 in brains of patients with Alzheimer's disease and controls.
Academic Article Amyloid production and deposition in mutant amyloid precursor protein and presenilin-1 yeast artificial chromosome transgenic mice.
Academic Article Neuroscience. An accomplice for gamma-secretase brought into focus.
Academic Article Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1.
Academic Article Dual roles for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing.
Academic Article Enhanced synaptic potentiation in transgenic mice expressing presenilin 1 familial Alzheimer's disease mutation is normalized with a benzodiazepine.
Academic Article Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease.
Academic Article The value of transgenic models for the study of neurodegenerative diseases.
Academic Article Familial British dementia: expression and metabolism of BRI.
Academic Article Function and dysfunction of the presenilins.
Academic Article Characterization of a presenilin-mediated amyloid precursor protein carboxyl-terminal fragment gamma. Evidence for distinct mechanisms involved in gamma -secretase processing of the APP and Notch1 transmembrane domains.
Academic Article Biomedicine. A cargo receptor mystery APParently solved?
Academic Article Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.
Academic Article Identification of the presenilins in hematopoietic cells with localization of presenilin 1 to neutrophil and platelet granules.
Academic Article Gamma-secretase: never more enigmatic.
Academic Article gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?
Academic Article Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.
Academic Article Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein.
Academic Article Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides.
Academic Article Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice.
Academic Article Familial Alzheimer disease-linked presenilin 1 variants enhance production of both Abeta 1-40 and Abeta 1-42 peptides that are only partially sensitive to a potent aspartyl protease transition state inhibitor of "gamma-secretase".
Academic Article Cell-free generation of the notch1 intracellular domain (NICD) and APP-CTfgamma: evidence for distinct intramembranous "gamma-secretase" activities.
Academic Article Presenilin-dependent "gamma-secretase" processing of deleted in colorectal cancer (DCC).
Academic Article Presenilin-1 regulates intracellular trafficking and cell surface delivery of beta-amyloid precursor protein.
Academic Article Regulated hyperaccumulation of presenilin-1 and the "gamma-secretase" complex. Evidence for differential intramembranous processing of transmembrane subatrates.
Academic Article DNA microarray profiling of developing PS1-deficient mouse brain reveals complex and coregulated expression changes.
Academic Article Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway.
Academic Article Spatial segregation of gamma-secretase and substrates in distinct membrane domains.
Academic Article True and false discovery in DNA microarray experiments: transcriptome changes in the hippocampus of presenilin 1 mutant mice.
Academic Article Presenilin attenuates receptor-mediated signaling and synaptic function.
Academic Article Presenilin-1-dependent transcriptome changes.
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 Expression of a familial Alzheimer's disease-linked presenilin-1 variant enhances perforant pathway lesion-induced neuronal loss in the entorhinal cortex.
Academic Article Presenilin 1 in migration and morphogenesis in the central nervous system.
Academic Article P75 neurotrophin receptor regulates expression of neural cell adhesion molecule 1.
Academic Article Transcriptome differences between the frontal cortex and hippocampus of wild-type and humanized presenilin-1 transgenic mice.
Academic Article Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons.
Academic Article Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.
Academic Article Structure of gamma-secretase and its trimeric pre-activation intermediate by single-particle electron microscopy.
Academic Article Activation and intrinsic gamma-secretase activity of presenilin 1.
Academic Article Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes.
Academic Article Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited.
Academic Article Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.
Academic Article Stable association of presenilin derivatives and absence of presenilin interactions with APP.
Academic Article Alzheimer's disease: perspectives for the new millennium.
Academic Article Subcellular localization of presenilins: association with a unique membrane pool in cultured cells.
Academic Article The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage.
Academic Article The topology of pen-2, a ?-secretase subunit, revisited: evidence for a reentrant loop and a single pass transmembrane domain.
Academic Article Evidence That the "Lid" Domain of Nicastrin Is Not Essential for Regulating ?-Secretase Activity.

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