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One or more keywords matched the following properties of Sisodia, Sangram S.
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 Amyloid
Concept Amyloid beta-Protein Precursor
Concept Plaque, Amyloid
Concept Amyloid Neuropathies
Concept Amyloid beta-Peptides
Concept Amyloid Precursor Protein Secretases
Academic Article Defective neurite extension is caused by a mutation in amyloid beta/A4 (A beta) protein precursor found in familial Alzheimer's disease.
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 Metabolism of the "Swedish" amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the "beta-secretase" site occurs in the golgi apparatus.
Academic Article Studies on the metabolism and biological function of APLP2.
Academic Article The profile of soluble amyloid beta protein in cultured cell media. Detection and quantification of amyloid beta protein and variants by immunoprecipitation-mass spectrometry.
Academic Article Expression of presenilin 1 and 2 (PS1 and PS2) in human and murine tissues.
Academic Article Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
Academic Article Expression of mutant amyloid precursor proteins induces apoptosis in PC12 cells.
Academic Article A role for amyloid precursor-like protein 2 in corneal epithelial wound healing.
Academic Article Mice deficient for the amyloid precursor protein gene.
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 Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.
Academic Article Amyloidosis in aging and Alzheimer's disease.
Academic Article Protein topology of presenilin 1.
Academic Article A role for the beta-amyloid precursor protein in memory?
Academic Article Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.
Academic Article Amyloidogenesis in Alzheimer's disease: basic biology and animal models.
Academic Article Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations.
Academic Article Inherited neurodegenerative diseases and transgenic models.
Academic Article Alzheimer disease--when and why?
Academic Article Amyloid precursor-like protein 2 promotes cell migration toward fibronectin and collagen IV.
Academic Article Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path.
Academic Article Alzheimer's disease: genetic studies and transgenic models.
Academic Article Expression and distribution of amyloid precursor protein-like protein-2 in Alzheimer's disease and in normal brain.
Academic Article Toxicity of synthetic A beta peptides and modeling of Alzheimer's disease.
Academic Article Familial amyotrophic lateral sclerosis and Alzheimer's disease. Transgenic models.
Academic Article Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins.
Academic Article Genetic neurodegenerative diseases: the human illness and transgenic models.
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 Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides.
Academic Article Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation.
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 Mice with combined gene knock-outs reveal essential and partially redundant functions of amyloid precursor protein family members.
Academic Article Requirement for presenilin 1 in facilitating lagged 2-mediated endoproteolysis and signaling of notch 1.
Academic Article Post-translational processing and turnover kinetics of presynaptically targeted amyloid precursor superfamily proteins in the central nervous system.
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 Altered metabolism of familial Alzheimer's disease-linked amyloid precursor protein variants in yeast artificial chromosome transgenic mice.
Academic Article Evidence that beta-amyloid protein in Alzheimer's disease is not derived by normal processing.
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 Gamma-secretase: never more enigmatic.
Academic Article gamma-Secretase, Notch, Abeta and Alzheimer's disease: where do the presenilins fit in?
Academic Article Multiple effects of aspartate mutant presenilin 1 on the processing and trafficking of amyloid precursor protein.
Academic Article Aged non-human primates: an animal model of age-associated neurodegenerative disease.
Academic Article Proteolytic processing of familial British dementia-associated BRI variants: evidence for enhanced intracellular accumulation of amyloidogenic peptides.
Academic Article Neurofibrillary tangles and beta-amyloid deposits in Alzheimer's disease.
Academic Article Accumulation of proteolytic fragments of mutant presenilin 1 and accelerated amyloid deposition are co-regulated in transgenic mice.
Academic Article Evidence that synaptically released beta-amyloid accumulates as extracellular deposits in the hippocampus of 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 Post-translational processing of beta-secretase (beta-amyloid-converting enzyme) and its ectodomain shedding. The pro- and transmembrane/cytosolic domains affect its cellular activity and amyloid-beta production.
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 APP processing and synaptic function.
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 Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.
Academic Article Studies on the proteolytic degradation of the beta-protein precursor by proteases purified from Alzheimer's disease brain.
Academic Article Evidence that assembly of an active gamma-secretase complex occurs in the early compartments of the secretory pathway.
Academic Article A sequence within the first transmembrane domain of PEN-2 is critical for PEN-2-mediated endoproteolysis of presenilin 1.
Academic Article Spatial segregation of gamma-secretase and substrates in distinct membrane domains.
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 Differential expression of amyloid precursor protein mRNAs in cases of Alzheimer's disease and in aged nonhuman primates.
Academic Article Nigrostriatal dysfunction in familial Alzheimer's disease-linked APPswe/PS1DeltaE9 transgenic mice.
Academic Article Neuronal responses to injury and aging: lessons from animal models.
Academic Article Cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three APP family members.
Academic Article Amyloid precursor protein in aged nonhuman primates.
Academic Article AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.
Academic Article Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin).
Academic Article Presenilin 1 in migration and morphogenesis in the central nervous system.
Academic Article Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells.
Academic Article Amyloid-related proteins and nerve growth factor in Alzheimer's disease and animal models.
Academic Article Enhanced accumulation of phosphorylated alpha-synuclein and elevated beta-amyloid 42/40 ratio caused by expression of the presenilin-1 deltaT440 mutant associated with familial Lewy body disease and variant Alzheimer's disease.
Academic Article Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis.
Academic Article Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons.
Academic Article Evidence that the "NF" motif in transmembrane domain 4 of presenilin 1 is critical for binding with PEN-2.
Academic Article Presenilin-1 uses phospholipase D1 as a negative regulator of beta-amyloid formation.
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 Amyloid beta from axons and dendrites reduces local spine number and plasticity.
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 Identification of NEEP21 as a ß-amyloid precursor protein-interacting protein in vivo that modulates amyloidogenic processing in vitro.
Academic Article Increased expression of PS1 is sufficient to elevate the level and activity of ?-secretase in vivo.
Academic Article BMS-708,163 targets presenilin and lacks notch-sparing activity.
Academic Article Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited.
Academic Article Expression, purification, and characterization of the Kunitz-type proteinase inhibitor domain of the amyloid beta-protein precursor-like protein-2.
Academic Article Role of the beta-amyloid protein in Alzheimer's disease.
Academic Article Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site.
Academic Article Trafficking and proteolytic processing of APP.
Academic Article Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain.
Academic Article Secretion of the beta-amyloid precursor protein.
Academic Article Alzheimer disease and the prion disorders amyloid beta-protein and prion protein amyloidoses.
Academic Article Cellular and molecular biology of Alzheimer's disease and animal models.
Academic Article Regulated cleavage of Alzheimer beta-amyloid precursor protein in the absence of the cytoplasmic tail.
Academic Article Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system.
Academic Article Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of ?-secretase using synthetic antibodies.
Academic Article Amyloid beta amyloidosis in Alzheimer's disease.
Academic Article Cellular and molecular biology of Alzheimer's disease and animal models.
Academic Article Metabolism of the amyloid precursor-like protein 2 in MDCK cells. Polarized trafficking occurs independent of the chondroitin sulfate glycosaminoglycan chain.
Academic Article A mouse model for Down syndrome exhibits learning and behaviour deficits.
Academic Article The mouse APLP2 gene. Chromosomal localization and promoter characterization.
Academic Article Altered processing of a mutant amyloid precursor protein in neuronal and endothelial cells.
Academic Article Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected].
Academic Article Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.
Academic Article Metabolism of the "Swedish" amyloid precursor protein variant in Madin-Darby canine kidney cells.
Academic Article Isolation and characterization of APLP2 encoding a homologue of the Alzheimer's associated amyloid beta protein precursor.
Academic Article Alzheimer's disease-type brain abnormalities in animal models.
Academic Article cDNA cloning and chromosome mapping of the human Fe65 gene: interaction of the conserved cytoplasmic domains of the human beta-amyloid precursor protein and its homologues with the mouse Fe65 protein.
Academic Article Cellular and molecular genetic approaches in Alzheimer's disease.
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 APP transgenic mice Tg2576 accumulate Abeta peptides that are distinct from the chemically modified and insoluble peptides deposited in Alzheimer's disease senile plaques.
Academic Article The Notch ligands, Delta1 and Jagged2, are substrates for presenilin-dependent "gamma-secretase" cleavage.
Academic Article Expression of a ubiquitous, cross-reactive homologue of the mouse beta-amyloid precursor protein (APP).
Academic Article Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE.
Academic Article Plug-based microfluidics with defined surface chemistry to miniaturize and control aggregation of amyloidogenic peptides.
Academic Article Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells.
Academic Article Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2.
Academic Article Comment on "ApoE-directed therapeutics rapidly clear ß-amyloid and reverse deficits in AD mouse models".
Academic Article A synthetic antibody fragment targeting nicastrin affects assembly and trafficking of ?-secretase.
Academic Article Nontranscriptional role of Hif-1a in activation of ?-secretase and notch signaling in breast cancer.
Academic Article Differential release of ß-amyloid from dendrite- versus axon-targeted APP.
Academic Article Acne inversa caused by missense mutations in NCSTN is not fully compatible with impairments in Notch signaling.
Academic Article Soluble ?-secretase modulators selectively inhibit the production of the 42-amino acid amyloid ß peptide variant and augment the production of multiple carboxy-truncated amyloid ß species.
Academic Article Age-dependent, non-cell-autonomous deposition of amyloid from synthesis of ß-amyloid by cells other than excitatory neurons.
Academic Article Amyloid Precursor-like Protein 2 and Sortilin Do Not Regulate the PCSK9 Convertase-mediated Low Density Lipoprotein Receptor Degradation but Interact with Each Other.
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.
Academic Article Microglia turnover with aging and in an Alzheimer's model via long-term in vivo single-cell imaging.
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 Negative evidence for a role of APH1B T27I variant in Alzheimer's disease.
Academic Article Alternatives to amyloid for Alzheimer's disease therapies-a symposium report.
Academic Article An APP ectodomain mutation outside of the Aß domain promotes Aß production in vitro and deposition in vivo.
Academic Article Nanoscale organization of Nicastrin, the substrate receptor of the ?-secretase complex, as independent molecular domains.
Academic Article Gut microbiota-driven brain Aß amyloidosis in mice requires microglia.
Academic Article Increased Type I interferon signaling and brain endothelial barrier dysfunction in an experimental model of Alzheimer's disease.
Academic Article The gut microbiome in Alzheimer's disease: what we know and what remains to be explored.
Academic Article The gut microbiome regulates astrocyte reaction to Aß amyloidosis through microglial dependent and independent mechanisms.
Academic Article Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome.
Academic Article Early modulation of the gut microbiome by female sex hormones alters amyloid pathology and microglial function.
Academic Article Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner.
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  • Amyloid