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Sisodia, Sangram S.
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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.
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Concept Amyotrophic Lateral Sclerosis
Concept Aged, 80 and over
Concept Aged
Concept Amino Acid Sequence
Concept Adult
Concept Cell Line, Transformed
Concept Animals
Concept Animals, Newborn
Concept Axonal Transport
Concept Base Sequence
Concept Aspartic Acid
Concept Biological Transport
Concept Cattle
Concept Central Nervous System
Concept Cell-Free System
Concept Genetic Vectors
Concept Cricetulus
Concept Cross-Linking Reagents
Concept Homozygote
Concept Dogs
Concept Chromatography, High Pressure Liquid
Concept Family
Concept Mice, Inbred C3H
Concept Frontal Lobe
Concept Genes, Lethal
Concept Half-Life
Concept Nucleic Acid Hybridization
Concept Lanosterol
Concept Life Expectancy
Concept Lipoproteins
Concept Enzyme-Linked Immunosorbent Assay
Concept Light
Concept Macaca
Concept Macaca mulatta
Concept Mammals
Concept Mice, Inbred CBA
Concept Mice, Neurologic Mutants
Concept Mice, Transgenic
Concept Prions
Concept Molecular Sequence Data
Concept Mice, Inbred C57BL
Concept Mice, Nude
Concept Middle Aged
Concept Repetitive Sequences, Nucleic Acid
Concept Cricetinae
Concept Nervous System Diseases
Concept Lidocaine
Concept Ligands
Concept Lipid Bilayers
Concept Liver
Concept Lung Neoplasms
Concept Peripheral Nervous System Diseases
Concept Membrane Lipids
Concept Primates
Concept Image Processing, Computer-Assisted
Concept Rabbits
Concept Receptors, LDL
Concept Sindbis Virus
Concept Saimiri
Concept Humans
Concept Caenorhabditis elegans
Concept Sequence Homology, Amino Acid
Concept Lysosomes
Concept Gene Library
Concept Glutamic Acid
Concept Lateral Ventricles
Concept Aspartic Acid Endopeptidases
Concept Second Messenger Systems
Concept Genomic Library
Concept Rats, Sprague-Dawley
Concept Mice, Knockout
Concept Excitatory Amino Acid Antagonists
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Concept Amino Acid Transport System X-AG
Concept Chromosomes, Artificial, Yeast
Concept Palmitic Acid
Concept Amino Acid Substitution
Concept Heredodegenerative Disorders, Nervous System
Concept Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Concept Amino Acid Motifs
Concept Databases, Genetic
Concept Transport Vesicles
Concept Animals, Genetically Modified
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Concept Saccharomyces cerevisiae
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Concept Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Concept Two-Hybrid System Techniques
Concept Basic Helix-Loop-Helix Transcription Factors
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Concept Adaptor Proteins, Vesicular Transport
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 Loss of functional prion protein: a role in prion disorders?
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 Neurodegenerative diseases and model systems.
Academic Article Neuronal degeneration in human diseases and animal models.
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 Motor neuron disease and model systems: aetiologies, mechanisms and therapies.
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 Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.
Academic Article Generation of APLP2 KO mice and early postnatal lethality in APLP2/APP double KO mice.
Academic Article Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease.
Academic Article Ectodomain phosphorylation of beta-amyloid precursor protein at two distinct cellular locations.
Academic Article Inherited neurodegenerative diseases and transgenic models.
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 Evidence that levels of presenilins (PS1 and PS2) are coordinately regulated by competition for limiting cellular factors.
Academic Article Alzheimer amyloid protein precursor in the rat hippocampus: transport and processing through the perforant path.
Academic Article An Alzheimer's disease-linked PS1 variant rescues the developmental abnormalities of PS1-deficient embryos.
Academic Article ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions.
Academic Article Lack of requirement for presenilin1 in Notch1 signaling.
Academic Article Familial amyotrophic lateral sclerosis and Alzheimer's disease. Transgenic models.
Academic Article Endoproteolytic processing and stabilization of wild-type and mutant presenilin.
Academic Article Identification and characterization of a mouse homologue of the spinal muscular atrophy-determining gene, survival motor neuron.
Academic Article Genetic neurodegenerative diseases: the human illness and transgenic models.
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 Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation.
Academic Article Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm.
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 Amyotrophic lateral sclerosis and Alzheimer disease. Lessons from model systems.
Academic Article Dual roles for Ste24p in yeast a-factor maturation: NH2-terminal proteolysis and COOH-terminal CAAX processing.
Academic Article Post-translational processing and turnover kinetics of presynaptically targeted amyloid precursor superfamily proteins in the central nervous system.
Academic Article Nuclear inclusions in glutamine repeat disorders: are they pernicious, coincidental, or beneficial?
Academic Article Amyloid precursor proteins inhibit heme oxygenase activity and augment neurotoxicity in Alzheimer's disease.
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 Axonal transport of mutant superoxide dismutase 1 and focal axonal abnormalities in the proximal axons of transgenic mice.
Academic Article Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis.
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 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 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 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 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 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 Biogenesis of gamma-secretase early in the secretory pathway.
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 AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss.
Academic Article Presenilin 1 in migration and morphogenesis in the central nervous system.
Academic Article Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1.
Academic Article Secretion of the beta/A4 amyloid precursor protein. Identification of a cleavage site in cultured mammalian cells.
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 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 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 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 An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria.
Academic Article Expression, purification, and characterization of the Kunitz-type proteinase inhibitor domain of the amyloid beta-protein precursor-like protein-2.
Academic Article Amyloid precursor-like protein 2 (APLP2) is modified by the addition of chondroitin sulfate glycosaminoglycan at a single site.
Academic Article Expression of familial Alzheimer's disease-linked human presenilin 1 variants impair enrichment-induced adult hippocampal neurogenesis.
Academic Article Trafficking and proteolytic processing of APP.
Academic Article A role for presenilins in autophagy revisited: normal acidification of lysosomes in cells lacking PSEN1 and PSEN2.
Academic Article Characterization of sorting signals in the beta-amyloid precursor protein cytoplasmic domain.
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 Rapid anterograde axonal transport of the cellular prion glycoprotein in the peripheral and central nervous systems.
Academic Article Identification of a tetratricopeptide repeat-like domain in the nicastrin subunit of ?-secretase using synthetic antibodies.
Academic Article Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons.
Academic Article Neuronal disorders: studies of animal models and human diseases.
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 Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells.
Academic Article Altered processing of a mutant amyloid precursor protein in neuronal and endothelial cells.
Academic Article Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function.
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 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 Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.
Academic Article Subcellular localization of presenilins: association with a unique membrane pool in cultured cells.
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 In vivo discrimination among beta-tubulin isotypes: selective degradation of a type IV beta-tubulin isotype following overexpression in cultured animal cells.
Academic Article Structure of substrate-free human insulin-degrading enzyme (IDE) and biophysical analysis of ATP-induced conformational switch of IDE.
Academic Article Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling.
Academic Article Heterogeneity of CNS myeloid cells and their roles in neurodegeneration.
Academic Article Axonal transport of APP and the spatial regulation of APP cleavage and function in neuronal cells.
Academic Article Specificity of RNA maturation pathways: RNAs transcribed by RNA polymerase III are not substrates for splicing or polyadenylation.
Academic Article Novel regulation of chondroitin sulfate glycosaminoglycan modification of amyloid precursor protein and its homologue, APLP2.
Academic Article Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity.
Academic Article Evidence of discontinuous transcription in the trypanosomatid Crithidia fasciculata.
Academic Article Autoregulatory control of beta-tubulin mRNA stability is linked to translation elongation.
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 Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors.
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 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 Deficits in Enrichment-Dependent Neurogenesis and Enhanced Anxiety Behaviors Mediated by Expression of Alzheimer's Disease-Linked Ps1 Variants Are Rescued by Microglial Depletion.
Academic Article DNA-based fluorescent probes of NOS2 activity in live brains.
Academic Article An APP ectodomain mutation outside of the Aß domain promotes Aß production in vitro and deposition in vivo.
Concept Gene Ontology
Concept Microbiota
Academic Article Donald Lowell Price, M.D. In memoriam.
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