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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 Alzheimer Disease
Academic Article Transgenic models of neurodegenerative diseases.
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 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 Neurodegenerative diseases and model systems.
Academic Article Familial Alzheimer's disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo.
Academic Article Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides.
Academic Article Amyloidosis in aging and Alzheimer's disease.
Academic Article A role for the beta-amyloid precursor protein in memory?
Academic Article Amyloidogenesis in Alzheimer's disease: basic biology and animal models.
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 Alzheimer disease--when and why?
Academic Article Amyloid precursor-like protein 2 promotes cell migration toward fibronectin and collagen IV.
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 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 Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides.
Academic Article Synaptic transmission and hippocampal long-term potentiation in transgenic mice expressing FAD-linked presenilin 1.
Academic Article Processing of presenilin 1 in brains of patients with Alzheimer's disease and controls.
Academic Article Mutant genes in familial Alzheimer's disease and transgenic models.
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 Amyotrophic lateral sclerosis and Alzheimer disease. Lessons from model systems.
Academic Article Post-translational processing and turnover kinetics of presynaptically targeted amyloid precursor superfamily proteins in the central nervous system.
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 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 Transgenic mouse models of Alzheimer's disease and amyotrophic lateral sclerosis.
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 Upregulation of BiP and CHOP by the unfolded-protein response is independent of presenilin expression.
Academic Article Aged non-human primates: an animal model of age-associated neurodegenerative disease.
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 APP processing and synaptic function.
Academic Article Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.
Academic Article DNA microarray profiling of developing PS1-deficient mouse brain reveals complex and coregulated expression changes.
Academic Article Studies on the proteolytic degradation of the beta-protein precursor by proteases purified from Alzheimer's disease brain.
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 Adult neurogenesis is functionally associated with AD-like neurodegeneration.
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 Neuronal responses to injury and aging: lessons from animal models.
Academic Article Presenilins and Alzheimer disease: the calcium conspiracy.
Academic Article Accelerated Abeta deposition in APPswe/PS1deltaE9 mice with hemizygous deletions of TTR (transthyretin).
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 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 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 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 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 Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation.
Academic Article Pen2 and presenilin-1 modulate the dynamic equilibrium of presenilin-1 and presenilin-2 gamma-secretase complexes.
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 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 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 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 Amyloid beta amyloidosis in Alzheimer's disease.
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 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 Evidence that CD147 modulation of beta-amyloid (Abeta) levels is mediated by extracellular degradation of secreted Abeta.
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 Hyperaccumulation of FAD-linked presenilin 1 variants in vivo.
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 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 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 Mutant presenilin 1 expression in excitatory neurons impairs enrichment-mediated phenotypes of adult hippocampal progenitor cells.
Academic Article Comment on "ApoE-directed therapeutics rapidly clear ß-amyloid and reverse deficits in AD mouse models".
Academic Article Endogenous expression of FAD-linked PS1 impairs proliferation, neuronal differentiation and survival of adult hippocampal progenitors.
Academic Article Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease.
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 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 Negative evidence for a role of APH1B T27I variant in Alzheimer's disease.
Academic Article Synergistic depletion of gut microbial consortia, but not individual antibiotics, reduces amyloidosis in APPPS1-21 Alzheimer's transgenic mice.
Academic Article Alternatives to amyloid for Alzheimer's disease therapies-a symposium report.
Academic Article Alteration in synaptic nanoscale organization dictates amyloidogenic processing in Alzheimer's disease.
Academic Article An APP ectodomain mutation outside of the Aß domain promotes Aß production in vitro and deposition in vivo.
Academic Article BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology.
Academic Article Nanoscale organization of Nicastrin, the substrate receptor of the ?-secretase complex, as independent molecular domains.

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