Astrocyte Transforming Growth Factor Beta 1 Protects Synapses against Aβ Oligomers in Alzheimer's Disease Model

Alzheimer's disease (AD) is characterized by progressive cognitive decline, increasingly attributed to neuronal dysfunction induced by amyloid-β oligomers (AβOs). Although the impact of AβOs on neurons has been extensively studied, only recently have the possible effects of AβOs on astrocytes begun to be investigated. Given the key roles of astrocytes in synapse formation, plasticity, and function, we sought to investigate the impact of AβOs on astrocytes, and to determine whether this impact is related to the deleterious actions of AβOs on synapses. We found that AβOs interact with astrocytes, cause astrocyte activation and trigger abnormal generation of reactive oxygen species, which is accompanied by impairment of astrocyte neuroprotective potential in vitro. We further show that both murine and human astrocyte conditioned media (CM) increase synapse density, reduce AβOs binding, and prevent AβO-induced synapse loss in cultured hippocampal neurons. Both a neutralizing anti-transforming growth factor-β1 (TGF-β1) antibody and siRNA-mediated knockdown of TGF-β1, previously identified as an important synaptogenic factor secreted by astrocytes, abrogated the protective action of astrocyte CM against AβO-induced synapse loss. Notably, TGF-β1 prevented hippocampal dendritic spine loss and memory impairment in mice that received an intracerebroventricular infusion of AβOs. Results suggest that astrocyte-derived TGF-β1 is part of an endogenous mechanism that protects synapses against AβOs. By demonstrating that AβOs decrease astrocyte ability to protect synapses, our results unravel a new mechanism underlying the synaptotoxic action of AβOs in AD. SIGNIFICANCE STATEMENT Alzheimer's disease is characterized by progressive cognitive decline, mainly attributed to synaptotoxicity of the amyloid-β oligomers (AβOs). Here, we investigated the impact of AβOs in astrocytes, a less known subject. We show that astrocytes prevent synapse loss induced by AβOs, via production of transforming growth factor-β1 (TGF-β1). We found that AβOs trigger morphological and functional alterations in astrocytes, and impair their neuroprotective potential. Notably, TGF-β1 reduced hippocampal dendritic spine loss and memory impairment in mice that received intracerebroventricular infusions of AβOs. Our results describe a new mechanism underlying the toxicity of AβOs and indicate novel therapeutic targets for Alzheimer's disease, mainly focused on TGF-β1 and astrocytes.

[1]  F. Gomes,et al.  Interaction of amyloid-β (Aβ) oligomers with neurexin 2α and neuroligin 1 mediates synapse damage and memory loss in mice , 2017, The Journal of Biological Chemistry.

[2]  Manoj Kumar,et al.  INGE GRUNDKE-IQBAL AWARD FOR ALZHEIMER’S RESEARCH: NEUROTOXIC REACTIVE ASTROCYTES ARE INDUCED BY ACTIVATED MICROGLIA , 2019, Alzheimer's & Dementia.

[3]  S. Salomone,et al.  TGF-β1 prevents rat retinal insult induced by amyloid-β (1-42) oligomers. , 2016, European journal of pharmacology.

[4]  E. Hol,et al.  Astrogliosis: An integral player in the pathogenesis of Alzheimer's disease , 2016, Progress in Neurobiology.

[5]  Fabiana A. Caetano,et al.  Regulation of Amyloid β Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex* , 2016, The Journal of Biological Chemistry.

[6]  A. Verkhratsky,et al.  Astrocytes in physiological aging and Alzheimer’s disease , 2016, Neuroscience.

[7]  Ben A. Barres,et al.  Complement and microglia mediate early synapse loss in Alzheimer mouse models , 2016, Science.

[8]  W. Guo,et al.  Regulation of astrocyte pathology by fluoxetine prevents the deterioration of Alzheimer phenotypes in an APP/PS1 mouse model , 2016, Glia.

[9]  Guillermo E. Parada,et al.  Role of TGFβ signaling in the pathogenesis of Alzheimer’s disease , 2015, Front. Cell. Neurosci..

[10]  A. Palmeri,et al.  A key role for TGF-β1 in hippocampal synaptic plasticity and memory , 2015, Scientific Reports.

[11]  Yu-ping Peng,et al.  Protection of TGF-β1 against Neuroinflammation and Neurodegeneration in Aβ1–42-Induced Alzheimer’s Disease Model Rats , 2015, PloS one.

[12]  F. Gomes,et al.  Astrocytic control of neural circuit formation: Highlights on TGF-beta signaling , 2014, Neurochemistry International.

[13]  E. Hol,et al.  Isolation of glia from Alzheimer's mice reveals inflammation and dysfunction , 2014, Neurobiology of Aging.

[14]  F. Gomes,et al.  Astrocyte transforming growth factor beta 1 promotes inhibitory synapse formation via CaM kinase II signaling , 2014, Glia.

[15]  Brian C Coe,et al.  Alzheimer's Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates , 2014, The Journal of Neuroscience.

[16]  Yong Jeong,et al.  GABA from reactive astrocytes impairs memory in mouse models of Alzheimer's disease , 2014, Nature Medicine.

[17]  G. Ramírez,et al.  Age-dependent changes on TGFβ1 Smad3 pathway modify the pattern of microglial cell activation , 2014, Brain, Behavior, and Immunity.

[18]  D. Munoz,et al.  TNF-α mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer's β-amyloid oligomers in mice and monkeys. , 2013, Cell metabolism.

[19]  Beth Stevens,et al.  TGF-β Signaling Regulates Neuronal C1q Expression and Developmental Synaptic Refinement , 2013, Nature Neuroscience.

[20]  Kevin M. Curtis,et al.  Amyloid-β inhibits thrombospondin 1 release from cultured astrocytes: effects on synaptic protein expression. , 2013, Journal of neuropathology and experimental neurology.

[21]  W. Klein,et al.  Memantine Rescues Transient Cognitive Impairment Caused by High-Molecular-Weight Aβ Oligomers But Not the Persistent Impairment Induced by Low-Molecular-Weight Oligomers , 2013, The Journal of Neuroscience.

[22]  Ben A. Barres,et al.  Emerging roles of astrocytes in neural circuit development , 2013, Nature Reviews Neuroscience.

[23]  Michael Chen,et al.  Forebrain engraftment by human glial progenitor cells enhances synaptic plasticity and learning in adult mice. , 2013, Cell stem cell.

[24]  F. Saravia,et al.  Environmental enrichment prevents astroglial pathological changes in the hippocampus of APP transgenic mice, model of Alzheimer's disease , 2013, Experimental Neurology.

[25]  D. Foguel,et al.  Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice , 2012, Molecular Psychiatry.

[26]  M. Murphy,et al.  Targeting Astrocytes Ameliorates Neurologic Changes in a Mouse Model of Alzheimer's Disease , 2012, The Journal of Neuroscience.

[27]  Frank M LaFerla,et al.  Animal models of Alzheimer disease. , 2012, Cold Spring Harbor perspectives in medicine.

[28]  R. Panizzutti,et al.  Astrocyte-induced Synaptogenesis Is Mediated by Transforming Growth Factor β Signaling through Modulation of d-Serine Levels in Cerebral Cortex Neurons* , 2012, The Journal of Biological Chemistry.

[29]  E. Syková,et al.  Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease , 2012, Journal of anatomy.

[30]  L. Mucke,et al.  Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. , 2012, Cold Spring Harbor perspectives in medicine.

[31]  Stephen J. Smith,et al.  Astrocyte glypicans 4 and 6 promote formation of excitatory synapses via GluA1 AMPA receptors , 2012, Nature.

[32]  H. Brentani,et al.  Amyloid-β Oligomers Induce Differential Gene Expression in Adult Human Brain Slices* , 2012, The Journal of Biological Chemistry.

[33]  R. Panizzutti,et al.  TRANSFORMING GROWTH FACTOR BETA SIGNALING THROUGH MODULATION OF D-SERINE LEVELS IN CEREBRAL CORTEX NEURONS , 2012 .

[34]  A. Verkhratsky,et al.  Early astrocytic atrophy in the entorhinal cortex of a triple transgenic animal model of Alzheimer's disease , 2011, ASN neuro.

[35]  W. Klein,et al.  The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer’s disease , 2011, Neurobiology of Learning and Memory.

[36]  C. Alzheimer,et al.  More than being protective: functional roles for TGF-β/activin signaling pathways at central synapses , 2011, Trends in Neurosciences.

[37]  B. Barres,et al.  Control of excitatory CNS synaptogenesis by astrocyte-secreted proteins Hevin and SPARC , 2011, Proceedings of the National Academy of Sciences.

[38]  Alison Abbott,et al.  Dementia: A problem for our age , 2011, Nature.

[39]  A. Verkhratsky,et al.  Astrocytes in Alzheimer’s disease , 2010, Neurotherapeutics.

[40]  P. Frankland,et al.  Increased transforming growth factor-β1 modulates glutamate receptor expression in the hippocampus. , 2011, International journal of physiology, pathophysiology and pharmacology.

[41]  Ben A. Barres,et al.  Regulation of synaptic connectivity by glia , 2010, Nature.

[42]  F. Pitossi,et al.  Prenatal inflammation impairs adult neurogenesis and memory related behavior through persistent hippocampal TGFβ1 downregulation , 2010, Brain, Behavior, and Immunity.

[43]  A. Mcintyre,et al.  TGF-β2 alters the characteristics of the neuromuscular junction by regulating presynaptic quantal size , 2010, Proceedings of the National Academy of Sciences.

[44]  S. Ferreira,et al.  Amyloid-β Peptide Oligomers Disrupt Axonal Transport through an NMDA Receptor-Dependent Mechanism That Is Mediated by Glycogen Synthase Kinase 3β in Primary Cultured Hippocampal Neurons , 2010, The Journal of Neuroscience.

[45]  L. Mucke,et al.  Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks , 2010, Nature Neuroscience.

[46]  A. Verkhratsky,et al.  Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease , 2010, Glia.

[47]  J. Gewirtz,et al.  Canonical TGF-β Signaling Is Required for the Balance of Excitatory/Inhibitory Transmission within the Hippocampus and Prepulse Inhibition of Acoustic Startle , 2010, The Journal of Neuroscience.

[48]  Pierre J Magistretti,et al.  Amyloid-β Aggregates Cause Alterations of Astrocytic Metabolic Phenotype: Impact on Neuronal Viability , 2010, The Journal of Neuroscience.

[49]  R. Trullas,et al.  Amyloid beta oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. , 2010, Cell calcium.

[50]  H. Vankova,et al.  Transforming growth factor beta and soluble endoglin in the healthy senior and in Alzheimer’s disease patients , 2009, The journal of nutrition, health & aging.

[51]  Xiaohua Douglas Zhang,et al.  Inhibition of Calcineurin-mediated Endocytosis and α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors Prevents Amyloid β Oligomer-induced Synaptic Disruption , 2009, The Journal of Biological Chemistry.

[52]  G. Zamponi.  Faculty Opinions recommendation of Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. , 2009 .

[53]  John W. Gilbert,et al.  Cellular Prion Protein Mediates Impairment of Synaptic Plasticity by Amyloid-β Oligomers , 2009, Nature.

[54]  W. Klein,et al.  Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers , 2009, Proceedings of the National Academy of Sciences.

[55]  E. Bigio,et al.  Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers , 2008, Neurobiology of Aging.

[56]  L. Juliano,et al.  Amyloid-β Binds to the Extracellular Cysteine-rich Domain of Frizzled and Inhibits Wnt/β-Catenin Signaling* , 2008, Journal of Biological Chemistry.

[57]  W. Klein,et al.  Amyloid beta oligomers induce impairment of neuronal insulin receptors , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[58]  Weiqi Zhang,et al.  Loss of transforming growth factor-beta 2 leads to impairment of central synapse function , 2008, Neural Development.

[59]  D. Hess,et al.  Activity-dependent release of transforming growth factor-beta in a neuronal network in vitro , 2007, Neuroscience.

[60]  W. Klein,et al.  Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine* , 2007, Journal of Biological Chemistry.

[61]  Bernardo L Sabatini,et al.  Natural Oligomers of the Alzheimer Amyloid-β Protein Induce Reversible Synapse Loss by Modulating an NMDA-Type Glutamate Receptor-Dependent Signaling Pathway , 2007, The Journal of Neuroscience.

[62]  S. Love,et al.  Neurofibrillary Tangles May Interfere With Smad 2/3 Signaling in Neurons , 2007, Journal of neuropathology and experimental neurology.

[63]  E. Bigio,et al.  Monoclonal antibodies that target pathological assemblies of Aβ , 2007, Journal of neurochemistry.

[64]  J. Byrne,et al.  Transforming growth factor‐β2 modulates synaptic efficacy and plasticity and induces phosphorylation of CREB in hippocampal neurons , 2007, Hippocampus.

[65]  G. Perry,et al.  Ectopic expression of phospho‐Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor‐β pathway? , 2006, Journal of neuroscience research.

[66]  L. Mucke,et al.  Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology. , 2006, The Journal of clinical investigation.

[67]  T. Arendt,et al.  Altered subcellular location of phosphorylated Smads in Alzheimer's disease , 2006, The European journal of neuroscience.

[68]  C. Ali,et al.  Transforming growth factor-β signalling in brain disorders , 2006 .

[69]  C. Ali,et al.  Transforming growth factor-beta signalling in brain disorders. , 2006, Cytokine & growth factor reviews.

[70]  R. von Bernhardi,et al.  Expression of Scavenger Receptors in Glial Cells , 2005, Journal of Biological Chemistry.

[71]  J. Hell,et al.  Thrombospondins Are Astrocyte-Secreted Proteins that Promote CNS Synaptogenesis , 2005, Cell.

[72]  C. Finch,et al.  Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers , 2004, The Journal of Neuroscience.

[73]  F. Paoletti,et al.  Increased plasma levels of soluble CD40, together with the decrease of TGFβ1, as possible differential markers of Alzheimer disease , 2004, Experimental Gerontology.

[74]  Subhabrata Sanyal,et al.  Retrograde Regulation in the CNS Neuron-Specific Interpretations of TGF-β Signaling , 2004, Neuron.

[75]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[76]  T. Shirokawa,et al.  Specific uptake of Aβ1-40 in rat brain occurs in astrocyte, but not in microglia , 2003, Neuroscience Letters.

[77]  M. D'Andrea,et al.  Astrocytes accumulate Aβ42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains , 2003, Brain Research.

[78]  H. Hippius,et al.  The discovery of Alzheimer's disease , 2003, Dialogues in clinical neuroscience.

[79]  V. Budnik,et al.  Wnts and TGFβ in synaptogenesis: old friends signalling at new places , 2003, Nature Reviews Neuroscience.

[80]  T. Wyss-Coray,et al.  Adult mouse astrocytes degrade amyloid-beta in vitro and in situ. , 2003, Nature medicine.

[81]  V. Budnik,et al.  Wnts and TGF beta in synaptogenesis: old friends signalling at new places. , 2003, Nature reviews. Neuroscience.

[82]  Richard D. Fetter,et al.  wishful thinking Encodes a BMP Type II Receptor that Regulates Synaptic Growth in Drosophila , 2002, Neuron.

[83]  C. Göritz,et al.  CNS synaptogenesis promoted by glia-derived cholesterol. , 2001, Science.

[84]  A. Araque,et al.  Tripartite synapses: glia, the unacknowledged partner , 1999, Trends in Neurosciences.

[85]  T. Morgan,et al.  Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[86]  L. Ignarro,et al.  Cutting Edge: Antisense Knockdown of Inducible Nitric Oxide Synthase Inhibits Induction of Experimental Autoimmune Encephalomyelitis in SJL/J Mice , 1998, The Journal of Immunology.

[87]  L. Ignarro,et al.  Antisense knockdown of inducible nitric oxide synthase inhibits induction of experimental autoimmune encephalomyelitis in SJL/J mice. , 1998, Journal of immunology.

[88]  T. Beach,et al.  Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer's disease visual cortex , 1988, Brain Research.