The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Sangram S Sisodia - One of the best experts on this subject based on the ideXlab platform.
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cortical dysplasia resembling human type 2 lissencephaly in mice lacking all three app family members
The EMBO Journal, 2004Co-Authors: Jochen Herms, Sabine Ring, Brigitte Anliker, Sabine Heber, Martin Fuhrmann, Hans A Kretzschmar, Sangram S Sisodia, Ulrike MüllerAbstract:The Alzheimer's disease β-amyloid precursor protein (APP) is a member of a larger gene family that includes the amyloid precursor-like proteins, termed APLP1 and APLP2. We previously documented that APLP2−/−APLP1−/− and APLP2−/−APP−/− mice die postnatally, while APLP1−/−APP−/− mice and single mutants were viable. We now report that mice lacking all three APP/APLP family members survive through embryonic development, and die shortly after birth. In contrast to double-mutant animals with perinatal lethality, 81% of triple mutants showed cranial abnormalities. In 68% of triple mutants, we observed cortical dysplasias characterized by focal ectopic neuroblasts that had migrated through the basal lamina and pial membrane, a phenotype that resembles human type II lissencephaly. Moreover, at E18.5 triple mutants showed a partial loss of cortical Cajal Retzius (CR) cells, suggesting that APP/APLPs play a crucial role in the survival of CR cells and neuronal adhesion. Collectively, our data reveal an essential role for APP family members in normal brain development and early postnatal survival.
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mice with combined gene knock outs reveal essential and partially redundant functions of amyloid precursor protein family members
The Journal of Neuroscience, 2000Co-Authors: Sabine Heber, Jochen Herms, Hans A Kretzschmar, Sangram S Sisodia, Vladan Gajic, Johannes A Hainfellner, Adriano Aguzzi, Thomas Rulicke, Cornelia Von Koch, Phillippe TremmlAbstract:The amyloid precursor protein (APP) involved in Alzheimer's disease is a member of a larger gene family including amyloid precursor-like proteins APLP1 and APLP2. We generated and examined the phenotypes of mice lacking individual or all possible combinations of APP family members to assess potential functional redundancies within the gene family. Mice deficient for the nervous system-specific APLP1 protein showed a postnatal growth deficit as the only obvious abnormality. In contrast to this minor phenotype, APLP2(-/-)/APLP1(-/-) and APLP2(-/-)/APP(-/-) mice proved lethal early postnatally. Surprisingly, APLP1(-/-)/APP(-/-) mice were viable, apparently normal, and showed no compensatory upregulation of APLP2 expression. These data indicate redundancy between APLP2 and both other family members and corroborate a key physiological role for APLP2. This view gains further support by the observation that APLP1(-/-)/APP(-/-)/APLP2(+/-) mice display postnatal lethality. In addition, they provide genetic evidence for at least some distinct physiological roles of APP and APLP2 by demonstrating that combinations of single knock-outs with the APLP1 mutation resulted in double mutants of clearly different phenotypes, being either lethal, or viable. None of the lethal double mutants displayed, however, obvious histopathological abnormalities in the brain or any other organ examined. Moreover, cortical neurons from single or combined mutant mice showed unaltered survival rates under basal culture conditions and unaltered susceptibility to glutamate excitotoxicity in vitro.
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generation of APLP2 ko mice and early postnatal lethality in APLP2 app double ko mice
Neurobiology of Aging, 1997Co-Authors: C S Von Koch, Hui Zheng, Gopal Thinakaran, Donald L Price, Howard Y Chen, Myrna E Trumbauer, L H T Van Der Ploeg, Sangram S SisodiaAbstract:Abstract Amyloid precursor protein (APP) is a member of a larger gene family including amyloid precursor-like proteins (APLP), APLP2 and APLP1. To examine the function of APLP2 in vivo, we generated APLP2 knockout (KO) mice. They are of normal size, fertile, and appear healthy up to 22 months of age. We observed no impaired axonal outgrowth of olfactory sensory neurons following bulbectomy, suggesting against an important role for APLP2 alone in this process. Because APLP2 and APP are highly homologous and may serve similar functions in vivo, we generated mice with targeted APLP2 and APP alleles. Approximately 80% of double KO mice die within the first week after birth, suggesting that APLP2 and APP are required for early postnatal development. The surviving ∼20% of double KO mice are 20–30% reduced in weight and show difficulty in righting, ataxia, spinning behavior, and a head tilt, suggesting a deficit in balance and/or strength. Adult double KO mice mate poorly, despite apparent normal ovarian and testicular development. Otherwise, double KO mice appear healthy up to 13 months of age. We conclude, that APLP2 and APP can substitute for each other functionally.
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amyloid sz protein stimulates parallel increases in cellular levels of its precursor and amyloid precursor like protein 2 APLP2 in human cerebrovascular smooth muscle cells
Amyloid, 1997Co-Authors: Susan M Saporitoirwin, Gopal Thinakaran, Sangram S Sisodia, Lynda Ruffini, William E Van NostrandAbstract:The amyloid β-protein (Aβ) which accumulates in cerebral vascular and senile plaque deposits in the brains of patients with Alzheimer's disease (AD) is proteolytically derived from a larger precursor protein, the amyloid β-protein precursor (AβPP). AβPP is a member of a multigene family which includes amyloid precursor-like protein 2 (APLP2). Recently, we showed that Aβ1-42, but not the shorter Aβ1-40 induces cellular levels of AβPP in degenerating cultured human cerebrovascular smooth muscle (HCSM) cells. Here we report that Aβ1-42 stimulates a parallel increase in the cellular levels of APLP2 in cultured HCSM cells. in contrast, the levels of smooth muscle cell α-actin or total cellular protein did not appreciably change. These findings suggest a common regulatory mechanism for increased levels of HCSM cellular AJPP and APLP2 in response to pathologic Aβ1-42 induced stress.
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studies on the metabolism and biological function of APLP2
Annals of the New York Academy of Sciences, 1996Co-Authors: Sangram S Sisodia, Hui Zheng, Gopal Thinakaran, Hilda H Slunt, Cheryl A Kitt, C S Von Koch, Randall R Reed, Donald L PriceAbstract:Amyloid precursor proteins (APP) are a member of a larger family of proteins that include the amyloid precursor-like proteins (APLP) APLP1 and APLP2. We have examined the expression and metabolism of APLP2 and document that APLP2 is expressed at high levels in the nervous system and in peripheral tissues. Furthermore, several APLP2 isoforms encoded by alternatively spliced transcripts are posttranslationally modified by a chondroitin sulfate glycosaminoglycan (CSGAG) chain. Furthermore, CSGAG modification is regulated by the insertion of sequences encoded by an alternatively spliced exon. Notably, expression of the CSGAG form of APLP2 appears restricted to embryonic neurons and mature neuronal populations that undergo regeneration, such as olfactory sensory neurons. Thus, differences in posttranslational modifications between the APLP2 isoforms and APP are likely to underlie differences in the regulation and function of these homologues. Our present efforts are directed towards using gene targeting strategies to disrupt the expression of the mouse APP/APLP2 genes to define the normative roles of the encoded molecules in development, plasticity, regeneration, and repair.
Ulrike Müller - One of the best experts on this subject based on the ideXlab platform.
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appsα rescues impaired ca2 homeostasis in app and APLP2 deficient hippocampal neurons
Proceedings of the National Academy of Sciences of the United States of America, 2021Co-Authors: Susann Ludewig, Ulrike Müller, Ulrike Herrmann, Kristin Michaelsenpreusse, Kristin Metzdorf, Jennifer Just, Charlotte Bold, Martin KorteAbstract:Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer's disease-associated transgenes, presenilin and the amyloid precursor protein (APP). While intense research focused on amyloid-β-mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.
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lack of app and APLP2 in gabaergic forebrain neurons impairs synaptic plasticity and cognition
Cerebral Cortex, 2020Co-Authors: Annika Mehr, Martin Korte, Ulrike Herrmann, Susann Ludewig, Meike Hick, Michaela Kerstin Muller, Jakob Von Engelhardt, David P Wolfer, Ulrike MüllerAbstract:Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.
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amyloid precursor like proteins aplp1 and APLP2 are dispensable for normal development of the neonatal respiratory network
Frontiers in Molecular Neuroscience, 2017Co-Authors: Kang Han, Ulrike Müller, Swen HulsmannAbstract:Recent studies using animal models indicated that the members of the amyloid precursor protein (APP) gene family are important for the formation, maintenance, and plasticity of synapses. Despite this, the specific role of the APP homologues APLP1 and APLP2 within the CNS and PNS is still poorly understood. In contrast to the subtle phenotypes of single mutants, double knockout mice (DKO) lacking APP/APLP2 or APLP1/APLP2 die within the first day after birth. Whereas APP/APLP2-DKO mice show severe deficits of neuromuscular morphology and transmission, the underlying cause of lethality of APLP1/APLP2-DKO mice remains unclear. Since expression of both proteins was confirmed by in situ hybridization, we aimed to test the role of APLP1/APLP2 in the formation and maintenance of synapses in the brainstem, and assessed a potential dysfunction of the most vital central neuronal network in APLP1/APLP2-DKO mice by analyzing the respiratory network of the medulla. We performed in vivo unrestrained whole body plethysmography in newborn APLP1/APLP2-DKO mice at postnatal day zero. Additionally, we directly tested the activity of the respiratory network in an acute slice preparation that includes the pre-Botzinger complex. In both sets of experiments, no significant differences were detected regarding respiratory rate and cycle variability, strongly arguing against central respiratory problems as the primary cause of death of APLP1/APLP2-DKO mice. Thus, we conclude that APLP1 and APLP2 are dispensable for the development of the network and the generation of a normal breathing rhythm.
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not just amyloid physiological functions of the amyloid precursor protein family
Nature Reviews Neuroscience, 2017Co-Authors: Ulrike Müller, Thomas Deller, Martin KorteAbstract:Amyloid precursor protein (APP) has been heavily implicated in Alzheimer disease, but the physiological roles of APP and the related APP-like proteins (APLPs) remain less well understood. This Review examines the functions of the APP family and its fragments in CNS development, synaptic function, brain injury and ageing. Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.
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not just amyloid physiological functions of the amyloid precursor protein family
Nature Reviews Neuroscience, 2017Co-Authors: Ulrike Müller, Thomas Deller, Martin KorteAbstract:Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.
Joyce C Solheim - One of the best experts on this subject based on the ideXlab platform.
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APLP2 regulates the expression of mhc class i molecules on irradiated ewing s sarcoma cells
OncoImmunology, 2013Co-Authors: Haley L Peters, Ying Yan, Joyce C SolheimAbstract:Ewing’s sarcoma (EWS) is a pediatric cancer that is conventionally treated by surgery, chemotherapy, and radiation therapy. Innovative immunotherapies to treat EWS are currently under development. Unfortunately for EWS patients, when the disease is found to be resistant to current therapeutic approaches, the prognosis is predictably grim. Radiation therapy and immunotherapy could potentially synergize in the eradication of EWS, as some studies have previously shown that irradiation increases the presence of immune receptors, including MHC class I molecules, on the surface of tumor cells. However, EWS cells have been reported to express low levels of MHC class I molecules, a phenotype that would inhibit T-cell mediated lysis. We have previously demonstrated that the transgene-driven overexpression of amyloid β (A4) precursor-like protein 2 (APLP2) reduces the expression of MHC class I molecules on the surface of human cervical carcinoma HeLa cells. We thus examined whether endogenously expressed APLP2 down...
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Regulation of major histocompatibility complex class I molecule expression on cancer cells by amyloid precursor-like protein 2
Immunologic Research, 2011Co-Authors: Haley L Peters, Naava Naslavsky, Amit Tuli, Mahak Sharma, Steve Caplan, Richard G. Macdonald, Joyce C SolheimAbstract:The three members of the amyloid precursor protein family in mammals [amyloid precursor protein, amyloid precursor-like protein 1, and amyloid precursor-like protein 2 (APLP2)] have been implicated in a large array of intracellular processes, which include development, transcription, apoptosis, metabolism, and the cell cycle. A series of studies by our laboratories has demonstrated that APLP2 is highly expressed by many cancer cell lines (with the highest expression in pancreatic cancer cell lines) and that it facilitates major histocompatibility complex (MHC) class I molecule endocytosis. This review focuses on this recently revealed function of APLP2 relevant to tumor immunology: that it acts as a novel regulator of MHC class I molecule surface expression.
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mechanism for amyloid precursor like protein 2 enhancement of major histocompatibility complex class i molecule degradation
Journal of Biological Chemistry, 2009Co-Authors: Amit Tuli, Naava Naslavsky, Mahak Sharma, Haley L Capek, Steve Caplan, Joyce C SolheimAbstract:Earlier studies have demonstrated interaction of the murine major histocompatibility complex (MHC) class I molecule Kd with amyloid precursor-like protein 2 (APLP2), a ubiquitously expressed member of the amyloid precursor protein family. Our current findings indicate that APLP2 is internalized in a clathrin-dependent manner, as shown by utilization of inhibitors of the clathrin pathway. Furthermore, we demonstrated that APLP2 and Kd bind at the cell surface and are internalized together. The APLP2 cytoplasmic tail contains two overlapping consensus motifs for binding to the adaptor protein-2 complex, and mutation of a tyrosine shared by both motifs severely impaired APLP2 internalization and ability to promote Kd endocytosis. Upon increased expression of wild type APLP2, Kd molecules were predominantly directed to the lysosomes rather than recycled to the plasma membrane. These findings suggest a model in which APLP2 binds Kd at the plasma membrane, facilitates uptake of Kd in a clathrin-dependent manner, and routes the endocytosed Kd to the lysosomal degradation pathway. Thus, APLP2 has a multistep trafficking function that influences the expression of major histocompatibility complex class I molecules at the plasma membrane.
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amyloid precursor like protein 2 increases the endocytosis instability and turnover of the h2 kd mhc class i molecule
Journal of Immunology, 2008Co-Authors: Amit Tuli, Naava Naslavsky, Mahak Sharma, Steve Caplan, Joyce C Solheim, Mary M Mcilhaney, James E TalmadgeAbstract:The defense against the invasion of viruses and tumors relies on the presentation of viral and tumor-derived peptides to CTL by cell surface MHC class I molecules. Previously, we showed that the ubiquitously expressed protein amyloid precursor-like protein 2 (APLP2) associates with the folded form of the MHC class I molecule K d . In the current study, APLP2 was found to associate with folded K d molecules following their endocytosis and to increase the amount of endocytosed K d . In addition, increased expression of APLP2 was shown to decrease K d surface expression and thermostability. Correspondingly, K d thermostability and surface expression were increased by down-regulation of APLP2 expression. Overall, these data suggest that APLP2 modulates the stability and endocytosis of K d molecules.
Gopal Thinakaran - One of the best experts on this subject based on the ideXlab platform.
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APLP2 regulates refractive error and myopia development in mice and humans
PLOS Genetics, 2015Co-Authors: Andrei V Tkatchenko, Virginie J M Verhoeven, Jeremy A Guggenheim, Tatiana V Tkatchenko, Pirro G Hysi, Robert Wojciechowski, Pawan Kumar Singh, Ashok Kumar, Gopal Thinakaran, Cathy WilliamsAbstract:Myopia is the most common vision disorder and the leading cause of visual impairment worldwide. However, gene variants identified to date explain less than 10% of the variance in refractive error, leaving the majority of heritability unexplained (“missing heritability”). Previously, we reported that expression of APLP2 was strongly associated with myopia in a primate model. Here, we found that low-frequency variants near the 5’-end of APLP2 were associated with refractive error in a prospective UK birth cohort (n = 3,819 children; top SNP rs188663068, p = 5.0 × 10−4) and a CREAM consortium panel (n = 45,756 adults; top SNP rs7127037, p = 6.6 × 10−3). These variants showed evidence of differential effect on childhood longitudinal refractive error trajectories depending on time spent reading (gene x time spent reading x age interaction, p = 4.0 × 10−3). Furthermore, APLP2 knockout mice developed high degrees of hyperopia (+11.5 ± 2.2 D, p < 1.0 × 10−4) compared to both heterozygous (-0.8 ± 2.0 D, p < 1.0 × 10−4) and wild-type (+0.3 ± 2.2 D, p < 1.0 × 10−4) littermates and exhibited a dose-dependent reduction in susceptibility to environmentally induced myopia (F(2, 33) = 191.0, p < 1.0 × 10−4). This phenotype was associated with reduced contrast sensitivity (F(12, 120) = 3.6, p = 1.5 × 10−4) and changes in the electrophysiological properties of retinal amacrine cells, which expressed APLP2. This work identifies APLP2 as one of the “missing” myopia genes, demonstrating the importance of a low-frequency gene variant in the development of human myopia. It also demonstrates an important role for APLP2 in refractive development in mice and humans, suggesting a high level of evolutionary conservation of the signaling pathways underlying refractive eye development.
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generation of APLP2 ko mice and early postnatal lethality in APLP2 app double ko mice
Neurobiology of Aging, 1997Co-Authors: C S Von Koch, Hui Zheng, Gopal Thinakaran, Donald L Price, Howard Y Chen, Myrna E Trumbauer, L H T Van Der Ploeg, Sangram S SisodiaAbstract:Abstract Amyloid precursor protein (APP) is a member of a larger gene family including amyloid precursor-like proteins (APLP), APLP2 and APLP1. To examine the function of APLP2 in vivo, we generated APLP2 knockout (KO) mice. They are of normal size, fertile, and appear healthy up to 22 months of age. We observed no impaired axonal outgrowth of olfactory sensory neurons following bulbectomy, suggesting against an important role for APLP2 alone in this process. Because APLP2 and APP are highly homologous and may serve similar functions in vivo, we generated mice with targeted APLP2 and APP alleles. Approximately 80% of double KO mice die within the first week after birth, suggesting that APLP2 and APP are required for early postnatal development. The surviving ∼20% of double KO mice are 20–30% reduced in weight and show difficulty in righting, ataxia, spinning behavior, and a head tilt, suggesting a deficit in balance and/or strength. Adult double KO mice mate poorly, despite apparent normal ovarian and testicular development. Otherwise, double KO mice appear healthy up to 13 months of age. We conclude, that APLP2 and APP can substitute for each other functionally.
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amyloid sz protein stimulates parallel increases in cellular levels of its precursor and amyloid precursor like protein 2 APLP2 in human cerebrovascular smooth muscle cells
Amyloid, 1997Co-Authors: Susan M Saporitoirwin, Gopal Thinakaran, Sangram S Sisodia, Lynda Ruffini, William E Van NostrandAbstract:The amyloid β-protein (Aβ) which accumulates in cerebral vascular and senile plaque deposits in the brains of patients with Alzheimer's disease (AD) is proteolytically derived from a larger precursor protein, the amyloid β-protein precursor (AβPP). AβPP is a member of a multigene family which includes amyloid precursor-like protein 2 (APLP2). Recently, we showed that Aβ1-42, but not the shorter Aβ1-40 induces cellular levels of AβPP in degenerating cultured human cerebrovascular smooth muscle (HCSM) cells. Here we report that Aβ1-42 stimulates a parallel increase in the cellular levels of APLP2 in cultured HCSM cells. in contrast, the levels of smooth muscle cell α-actin or total cellular protein did not appreciably change. These findings suggest a common regulatory mechanism for increased levels of HCSM cellular AJPP and APLP2 in response to pathologic Aβ1-42 induced stress.
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studies on the metabolism and biological function of APLP2
Annals of the New York Academy of Sciences, 1996Co-Authors: Sangram S Sisodia, Hui Zheng, Gopal Thinakaran, Hilda H Slunt, Cheryl A Kitt, C S Von Koch, Randall R Reed, Donald L PriceAbstract:Amyloid precursor proteins (APP) are a member of a larger family of proteins that include the amyloid precursor-like proteins (APLP) APLP1 and APLP2. We have examined the expression and metabolism of APLP2 and document that APLP2 is expressed at high levels in the nervous system and in peripheral tissues. Furthermore, several APLP2 isoforms encoded by alternatively spliced transcripts are posttranslationally modified by a chondroitin sulfate glycosaminoglycan (CSGAG) chain. Furthermore, CSGAG modification is regulated by the insertion of sequences encoded by an alternatively spliced exon. Notably, expression of the CSGAG form of APLP2 appears restricted to embryonic neurons and mature neuronal populations that undergo regeneration, such as olfactory sensory neurons. Thus, differences in posttranslational modifications between the APLP2 isoforms and APP are likely to underlie differences in the regulation and function of these homologues. Our present efforts are directed towards using gene targeting strategies to disrupt the expression of the mouse APP/APLP2 genes to define the normative roles of the encoded molecules in development, plasticity, regeneration, and repair.
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distribution of an app homolog APLP2 in the mouse olfactory system a potential role for APLP2 in axogenesis
The Journal of Neuroscience, 1995Co-Authors: Gopal Thinakaran, Hilda H Slunt, Cheryl A Kitt, C S Von Koch, Randall R Reed, A J Roskams, Eliezer Masliah, Stephen D Ginsberg, G V Ronnett, Donald L PriceAbstract:Deposition of beta-amyloid (A beta) in senile plaques is a major pathological characteristic of Alzheimer's disease. A beta is generated by proteolytic processing of amyloid precursor proteins (APP). APP is a member of a family of related polypeptides that includes amyloid precursor-like proteins APLP1 and APLP2. To examine the distribution of APLP2 in the nervous system, we generated antibodies specific for APLP2 and used these reagents in immunocytochemical and biochemical studies of the rodent nervous system. In this report, we document that in cortex and hippocampus, APLP2 is enriched in postsynaptic compartments. In the olfactory system, however, APLP2 is abundant in olfactory sensory axons, and axon terminals in glomeruli. Confocal microscopy revealed that APLP2 is present in both pre- and postsynaptic compartments in the olfactory bulb. Notably, mRNA encoding chondroitin sulfate glycosaminoglycan (CS GAG)-modified forms of APLP2 are enriched in the olfactory epithelium, relative to alternatively-spliced mRNA, encoding CS GAG-free forms of APLP2. In addition, we demonstrate that CS-modified APLP2 forms accumulate in the olfactory bulb. CS proteoglycans are known to play an important role in regulating cell migration and neuronal outgrowth. Since sensory neurons in the olfactory epithelium are in a state of continual turnover, axons of newly generated cells must establish synaptic connections with neurons in the olfactory bulb in adult life. The presence of APLP2 in olfactory sensory axons and glomeruli is consistent with the view that this protein may play an important role in axonal pathfinding and/or synaptogenesis.
Martin Korte - One of the best experts on this subject based on the ideXlab platform.
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appsα rescues impaired ca2 homeostasis in app and APLP2 deficient hippocampal neurons
Proceedings of the National Academy of Sciences of the United States of America, 2021Co-Authors: Susann Ludewig, Ulrike Müller, Ulrike Herrmann, Kristin Michaelsenpreusse, Kristin Metzdorf, Jennifer Just, Charlotte Bold, Martin KorteAbstract:Alterations in Ca2+ homeostasis have been reported in several in vitro and in vivo studies using mice expressing the Alzheimer's disease-associated transgenes, presenilin and the amyloid precursor protein (APP). While intense research focused on amyloid-β-mediated functions on neuronal Ca2+ handling, the physiological role of APP and its close homolog APLP2 is still not fully clarified. We now elucidate a mechanism to show how APP and its homolog APLP2 control neuronal Ca2+ handling and identify especially the ectodomain APPsα as an essential regulator of Ca2+ homeostasis. Importantly, we demonstrate that the loss of APP and APLP2, but not APLP2 alone, impairs Ca2+ handling, the refill of the endoplasmic reticulum Ca2+ stores, and synaptic plasticity due to altered function and expression of the SERCA-ATPase and expression of store-operated Ca2+ channel-associated proteins Stim1 and Stim2. Long-term AAV-mediated expression of APPsα, but not acute application of the recombinant protein, restored physiological Ca2+ homeostasis and synaptic plasticity in APP/APLP2 cDKO cultures. Overall, our analysis reveals an essential role of the APP family and especially of the ectodomain APPsα in Ca2+ homeostasis, thereby highlighting its therapeutic potential.
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lack of app and APLP2 in gabaergic forebrain neurons impairs synaptic plasticity and cognition
Cerebral Cortex, 2020Co-Authors: Annika Mehr, Martin Korte, Ulrike Herrmann, Susann Ludewig, Meike Hick, Michaela Kerstin Muller, Jakob Von Engelhardt, David P Wolfer, Ulrike MüllerAbstract:Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer’s disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity.
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not just amyloid physiological functions of the amyloid precursor protein family
Nature Reviews Neuroscience, 2017Co-Authors: Ulrike Müller, Thomas Deller, Martin KorteAbstract:Amyloid precursor protein (APP) has been heavily implicated in Alzheimer disease, but the physiological roles of APP and the related APP-like proteins (APLPs) remain less well understood. This Review examines the functions of the APP family and its fragments in CNS development, synaptic function, brain injury and ageing. Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.
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not just amyloid physiological functions of the amyloid precursor protein family
Nature Reviews Neuroscience, 2017Co-Authors: Ulrike Müller, Thomas Deller, Martin KorteAbstract:Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App-knockout and Aplp-knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuroprotection, as well as ageing. In addition, we discuss the implications of APP physiology for therapeutic approaches.
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fe65 and fe65l1 share common synaptic functions and genetically interact with the app family in neuromuscular junction formation
Scientific Reports, 2016Co-Authors: Paul Strecker, Susann Ludewig, Marco B Rust, Tabea A Mundinger, Andreas Gorlich, Elisa G Krachan, Christina Mehrfeld, Joachim Herz, Martin KorteAbstract:The FE65 adaptor proteins (FE65, FE65L1 and FE65L2) bind proteins that function in diverse cellular pathways and are essential for specific biological processes. Mice lacking both FE65 and FE65L1 exhibit ectopic neuronal positioning in the cortex and muscle weakness. p97FE65-KO mice, expressing a shorter FE65 isoform able to bind amyloid precursor protein family members (APP, APLP1, APLP2), develop defective long-term potentiation (LTP) and aged mice display spatial learning and memory deficits that are absent from young mice. Here, we examined the central and peripheral nervous systems of FE65-KO, FE65L1-KO and FE65/FE65L1-DKO mice. We find spatial learning and memory deficits in FE65-KO and FE65L1-KO mice. Severe motor impairments, anxiety, hippocampal LTP deficits and neuromuscular junction (NMJ) abnormalities, characterized by decreased size and reduced apposition of pre- and postsynaptic sites, are observed in FE65/FE65L1-DKO mice. As their NMJ deficits resemble those of mutant APP/APLP2-DKO mice lacking the FE65/FE65L1 binding site, the NMJs of APLP2/FE65-DKO and APLP2/FE65L1-DKO mice were analyzed. NMJ deficits are aggravated in these mice when compared to single FE65- and FE65L1-KO mice. Together, our data demonstrate a role for FE65 proteins at central and peripheral synapses possibly occurring downstream of cell surface-associated APP/APLPs.