Reelin and APP Cooperatively Modulate Dendritic Spine Formation In Vitro and In Vivo

Amyloid precursor protein (APP) plays an important role in the pathogenesis of Alzheimer’s disease (AD), but the normal function of APP at synapses is poorly understood. We and others have found that APP interacts with Reelin and that each protein is individually important for dendritic spine formation, which is associated with learning and memory, in vitro. However, whether Reelin acts through APP to modulate dendritic spine formation or synaptic function remains unknown. In the present study, we found that Reelin treatment significantly increased dendritic spine density and PSD-95 puncta number in primary hippocampal neurons. An examination of the molecular mechanisms by which Reelin regulates dendritic spinogenesis revealed that Reelin enhanced hippocampal dendritic spine formation in a Ras/ERK/CREB signaling-dependent manner. Interestingly, Reelin did not increase dendritic spine number in primary hippocampal neurons when APP expression was reduced or in vivo in APP knockout (KO) mice. Taken together, our data are the first to demonstrate that Reelin acts cooperatively with APP to modulate dendritic spine formation and suggest that normal APP function is critical for Reelin-mediated dendritic spinogenesis at synapses.

[1]  J. Herz,et al.  Reelin Regulates Neuronal Excitability through Striatal-Enriched Protein Tyrosine Phosphatase (STEP61) and Calcium Permeable AMPARs in an NMDAR-Dependent Manner , 2021, The Journal of Neuroscience.

[2]  Subhadip Basu,et al.  Quantification of Dendritic Spines Remodeling under Physiological Stimuli and in Pathological Conditions , 2021, International journal of molecular sciences.

[3]  P. Trifilieff,et al.  Age‐related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1 , 2020, Aging cell.

[4]  T. Sumi,et al.  Mechanism underlying hippocampal long-term potentiation and depression based on competition between endocytosis and exocytosis of AMPA receptors , 2020, Scientific Reports.

[5]  R. Chiesa,et al.  Mutant prion proteins increase calcium permeability of AMPA receptors, exacerbating excitotoxicity , 2020, PLoS pathogens.

[6]  Y. Jossin.  Reelin Functions, Mechanisms of Action and Signaling Pathways During Brain Development and Maturation , 2020, Biomolecules.

[7]  J. Sáez-Valero,et al.  Elevated Plasma Reelin Levels in Children With Autism , 2020, Frontiers in Psychiatry.

[8]  A. Draguhn,et al.  Amyloid, APP, and Electrical Activity of the Brain , 2019, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[9]  R. Turner,et al.  Polo-like kinase 2 phosphorylation of amyloid precursor protein regulates activity-dependent amyloidogenic processing , 2017, Neuropharmacology.

[10]  M. Marzolo,et al.  Interfering of the Reelin/ApoER2/PSD95 Signaling Axis Reactivates Dendritogenesis of Mature Hippocampal Neurons , 2017, Journal of cellular physiology.

[11]  Changwan Chen,et al.  Endocytosis of GluN2B-containing NMDA receptor mediates NMDA-induced excitotoxicity , 2017, Molecular pain.

[12]  J. Herms,et al.  Amyloid precursor protein maintains constitutive and adaptive plasticity of dendritic spines in adult brain by regulating D‐serine homeostasis , 2016, The EMBO journal.

[13]  P. Warne,et al.  RAS signalling through PI3-Kinase controls cell migration via modulation of Reelin expression , 2016, Nature Communications.

[14]  M. Lim,et al.  Association between RELN Gene Polymorphisms and Attention Deficit Hyperactivity Disorder in Korean Children , 2015, Psychiatry investigation.

[15]  I. Filonova,et al.  Reelin supplementation recovers synaptic plasticity and cognitive deficits in a mouse model for Angelman syndrome , 2015, The European journal of neuroscience.

[16]  J. Yates,et al.  Reelin Induces Erk1/2 Signaling in Cortical Neurons Through a Non-canonical Pathway* , 2014, The Journal of Biological Chemistry.

[17]  C. Pittenger,et al.  Creb Selectively Controls Learning-induced Structural Remodeling of Neurons Results Neuronal Localization of Mcreb , 2022 .

[18]  O. Arancio,et al.  β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia , 2012, Molecular Neurodegeneration.

[19]  J. Rogers,et al.  Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. , 2011, Learning & memory.

[20]  G. D’Arcangelo,et al.  Reelin deficiency causes specific defects in the molecular composition of the synapses in the adult brain , 2011, Neuroscience.

[21]  D. Pak,et al.  Requirement for Plk2 in Orchestrated Ras and Rap Signaling, Homeostatic Structural Plasticity, and Memory , 2011, Neuron.

[22]  Ryohei Yasuda,et al.  Local, persistent activation of Rho GTPases during plasticity of single dendritic spines , 2011, Nature.

[23]  M. Frotscher,et al.  Reelin Signals through Apolipoprotein E Receptor 2 and Cdc42 to Increase Growth Cone Motility and Filopodia Formation , 2010, The Journal of Neuroscience.

[24]  M. Frotscher,et al.  Role for Reelin‐induced cofilin phosphorylation in the assembly of sympathetic preganglionic neurons in the murine intermediolateral column , 2010, The European journal of neuroscience.

[25]  K. J. Lee,et al.  Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines , 2010, Neuroscience.

[26]  R. Nitsch,et al.  Reduced Reelin Expression Accelerates Amyloid-β Plaque Formation and Tau Pathology in Transgenic Alzheimer's Disease Mice , 2010, The Journal of Neuroscience.

[27]  M. Giustetto,et al.  Learning, AMPA receptor mobility and synaptic plasticity depend on n‐cofilin‐mediated actin dynamics , 2010, The EMBO journal.

[28]  Eduardo Soriano,et al.  Reelin Regulates Postnatal Neurogenesis and Enhances Spine Hypertrophy and Long-Term Potentiation , 2010, The Journal of Neuroscience.

[29]  R. Anwyl,et al.  Glun2b Subunit-containing Nmda Receptor Antagonists Prevent A␤-mediated Synaptic Plasticity Disruption in Vivo Abrogation of A␤-mediated Disruption of Hippocampal Synaptic Plasticity in Vivo by Antagonists Selective for Glun2b-containing , 2022 .

[30]  Songyang Zhou,et al.  Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis , 2009, The Journal of Neuroscience.

[31]  S. Rohn,et al.  FAD-mutation of APP is associated with a loss of its synaptotrophic activity , 2009, Neurobiology of Disease.

[32]  Guojun Bu,et al.  Interaction of Reelin with Amyloid Precursor Protein Promotes Neurite Outgrowth , 2009, The Journal of Neuroscience.

[33]  M. Ehlers,et al.  The Effects of Amyloid Precursor Protein on Postsynaptic Composition and Activity* , 2009, Journal of Biological Chemistry.

[34]  M. Frotscher,et al.  Reelin Stabilizes the Actin Cytoskeleton of Neuronal Processes by Inducing n-Cofilin Phosphorylation at Serine3 , 2009, The Journal of Neuroscience.

[35]  G. D’Arcangelo,et al.  The Reelin Signaling Pathway Promotes Dendritic Spine Development in Hippocampal Neurons , 2008, The Journal of Neuroscience.

[36]  W. Abraham,et al.  Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory , 2008, Neurobiology of Disease.

[37]  Karel Svoboda,et al.  The Spread of Ras Activity Triggered by Activation of a Single Dendritic Spine , 2008, Science.

[38]  A. Delacourte,et al.  Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity , 2007, Proceedings of the National Academy of Sciences.

[39]  L. Mucke,et al.  Reelin Depletion in the Entorhinal Cortex of Human Amyloid Precursor Protein Transgenic Mice and Humans with Alzheimer's Disease , 2007, The Journal of Neuroscience.

[40]  E. Weeber,et al.  Reelin signaling facilitates maturation of CA1 glutamatergic synapses. , 2007, Journal of neurophysiology.

[41]  L. Mao,et al.  Regulation of mitogen‐activated protein kinases by glutamate receptors , 2007, Journal of neurochemistry.

[42]  E. Weeber,et al.  Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus , 2006, The Journal of Neuroscience.

[43]  E. Weeber,et al.  Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice , 2006, Neurobiology of Learning and Memory.

[44]  J. D. del Río,et al.  Reelin expression and glycosylation patterns are altered in Alzheimer's disease. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Gang-yi Wu,et al.  Regulation of Dendritic Morphogenesis by Ras–PI3K–Akt–mTOR and Ras–MAPK Signaling Pathways , 2005, The Journal of Neuroscience.

[46]  P. Greengard,et al.  Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses , 2005, Neurobiology of Disease.

[47]  E. Weeber,et al.  Reelin, Very-Low-Density Lipoprotein Receptor, and Apolipoprotein E Receptor 2 Control Somatic NMDA Receptor Composition during Hippocampal Maturation In Vitro , 2005, The Journal of Neuroscience.

[48]  P. Greengard,et al.  The Amyloid Precursor Protein and Its Regulatory Protein, FE65, in Growth Cones and Synapses In Vitro and In Vivo , 2003, The Journal of Neuroscience.

[49]  J. Sweatt,et al.  Reelin and ApoE Receptors Cooperate to Enhance Hippocampal Synaptic Plasticity and Learning* , 2002, The Journal of Biological Chemistry.

[50]  R. Malinow,et al.  Ras and Rap Control AMPA Receptor Trafficking during Synaptic Plasticity , 2002, Cell.

[51]  P. Greengard,et al.  The Alzheimer Amyloid Precursor Protein (APP) and Fe65, an APP-Binding Protein, Regulate Cell Movement , 2001, The Journal of cell biology.

[52]  T. Curran,et al.  A protein related to extracellular matrix proteins deleted in the mouse mutant reeler , 1995, Nature.