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Prenatal infection: A novel link between brain development, inflammation and aging-associated neurodegeneration

English title Prenatal infection: A novel link between brain development, inflammation and aging-associated neurodegeneration
Applicant Knüsel Irene
Number 132629
Funding scheme Project funding
Research institution Institut für Pharmakologie und Toxikologie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2010 - 30.09.2013
Approved amount 288'000.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Immunology, Immunopathology

Keywords (32)

mus musculus; non-transgenic; prenatal infection; immune challenge; inflammation; cytokines and chemokines; Interleukin-1; Tumor-necrosis-factor alpha; PolyI:C; Hippocampal formation; amyloid-beta plaques; neurofibrillary tangles; neurodegeneration; microglia; astrocytes; Reelin; Apolipoprotein E receptor 2; Amyloid presursor protein; secretase; metalloproteinase; ADAMTS; Aging; cognitive decline; hippocampus; inflammatory cytokines; cell death; amyloid precursor protein; proteolytic processing; tau phosphorylation; mass spectrometry; electron microscopy; immunohistochemistry

Lay Summary (English)

Lead
Lay summary
Alzheimer's disease (AD) is the most common type of dementia, characterized by progressive neurodegeneration. Neuropathological hallmarks include proteinous aggregates in the form of amyloid-beta plaques and neurofibrillary tangles. Although investigations of the genetic basis of the disease have greatly enhanced our understanding of AD biology, dominant genetic mutations account only for a small percentage of cases. The majority are sporadic late-onset AD cases with largely unknown etiology. The fact that both forms of AD are characterized by the same neuropathological hallmarks points to the importance of modulatory factors involved in the pathophysiology of the disease.One of these potential modulators is Reelin, an extracellular glycoprotein with fundamental roles during brain development. This conserved protein is also a pivotal synaptic regulator which indirectly exerts broad control over synaptic function and plasticity in the adult brain. Recent data also demonstrated that Reelin-mediated signaling modulates both amyloid precursor protein (APP) processing and Tau phosphorylation.Our previous investigations provided evidence that Reelin itself forms amyloid-like plaques during aging and that these aggregates potentially reflect alterations in its proteolytic processing. This phenomenon is highly conserved since we detected it in aged rodents, non-human primates and postmortem human brain tissue. Our findings also revealed that a prenatal infection provokes a much earlier accumulation of Reelin-positive plaques and results in the formation of fibrillary amyloid-beta deposits that are associated with elevated levels of phosphorylated Tau protein in aged immune-challenged wild-type mice. These data provide the first evidence that a prenatal immune challenge is capable of inducing AD-like neuropathological hallmarks in aged wild type mice. Here, we propose to investigate the molecular mechanisms underlying the inflammation-induced dysfunctional Reelin signaling, the development of AD-like neuropathology and cognitive decline in mice. Specifically, we aim to determine the impact of pro-inflammatory cytokines on proteolytic cleavage of Reelin and its consequences on downstream signaling cascades involved in APP trafficking and amyloidogenic processing, as well as phosphorylation of Tau and neurofibrillary tangles formation. Through this, the project is expected to demonstrate that manipulation of inflammatory pathways altering the Reelin signaling pathway is a critical driving force of late-onset Alzheimer's disease pathology.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Decisive role of Reelin signaling during early stages of Alzheimer's disease.
Krstic Dimitrije, Pfister Sandra, Notter Tina, Knuesel Irene (2013), Decisive role of Reelin signaling during early stages of Alzheimer's disease., in Neuroscience, 246(C), 108-116.
Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout.
Muhia Mary, Willadt Silvia, Yee Benjamin K, Feldon Joram, Paterna Jean-Charles, Schwendener Severin, Vogt Kaspar, Kennedy Mary B, Knuesel Irene (2012), Molecular and behavioral changes associated with adult hippocampus-specific SynGAP1 knockout., in Learning & memory (Cold Spring Harbor, N.Y.), 19(7), 268-81.
Regulated Proteolytic Processing of Reelin through Interplay of Tissue Plasminogen Activator (tPA), ADAMTS-4, ADAMTS-5, and Their Modulators.
Krstic Dimitrije, Rodriguez Myriam, Knuesel Irene (2012), Regulated Proteolytic Processing of Reelin through Interplay of Tissue Plasminogen Activator (tPA), ADAMTS-4, ADAMTS-5, and Their Modulators., in PloS one, 7(10), 47793-47793.
Characterization and Turnover of CD73/IP 3 R3-positive Microvillar Cells in the Adult Mouse Olfactory Epithelium.
Pfister Sandra, Dietrich Maren G, Sidler Corinne, Fritschy Jean-Marc, Knuesel Irene, Elsaesser Rebecca (2012), Characterization and Turnover of CD73/IP 3 R3-positive Microvillar Cells in the Adult Mouse Olfactory Epithelium., in Chemical senses, 37(9), 859-68.
Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.
Krstic Dimitrije, Madhusudan Amrita, Doehner Jana, Vogel Prisca, Notter Tina, Imhof Claudine, Manalastas Abigail, Hilfiker Martina, Pfister Sandra, Schwerdel Cornelia, Riether Carsten, Meyer Urs, Knuesel Irene (2012), Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice., in Journal of neuroinflammation, 9(1), 151-151.
Extrusion of misfolded and aggregated proteins - a protective strategy of aging neurons?
Doehner Jana, Genoud Christel, Imhof Claudine, Krstic Dimitrije, Knuesel Irene (2012), Extrusion of misfolded and aggregated proteins - a protective strategy of aging neurons?, in The European journal of neuroscience, 35(12), 1938-50.
Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice.
Klohs Jan, Baltes Christof, Princz-Kranz Felicitas, Ratering David, Nitsch Roger M, Knuesel Irene, Rudin Markus (2012), Contrast-enhanced magnetic resonance microangiography reveals remodeling of the cerebral microvasculature in transgenic ArcAβ mice., in The Journal of neuroscience : the official journal of the Society for Neuroscience, 32(5), 1705-13.
Detection of cerebral microbleeds with quantitative susceptibility mapping in the ArcAbeta mouse model of cerebral amyloidosis.
Klohs J, Deistung A, Schweser F, Grandjean J, Dominietto M, Waschkies C, Nitsch RM, Knuesel I, Reichenbach JR, Rudin M (2011), Detection of cerebral microbleeds with quantitative susceptibility mapping in the ArcAbeta mouse model of cerebral amyloidosis., in J Cereb Blood Flow Metab., 31(22), 2282-2292.
Hippocampal pyramidal cells: the reemergence of cortical lamination
Slomianka L, Amrein I, Knuesel I, Sørensen JC, Wolfer DP (2011), Hippocampal pyramidal cells: the reemergence of cortical lamination, in Brain Struct Funct. , 216(4), 301-317.
Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy.
Duveau V, Madhusudan A, Caleo M, Knuesel I, Fritschy JM (2011), Impaired reelin processing and secretion by Cajal-Retzius cells contributes to granule cell dispersion in a mouse model of temporal lobe epilepsy., in Hippocampus, 21(9), 935 -944.
Prenatal infection as driving force of aging-associated neurodegenerative diseases.
Knuesel I (2011), Prenatal infection as driving force of aging-associated neurodegenerative diseases., in Praxis, 100(5), 299-304.
Deciphering the mechanism underyling late-onset Alzheimer's Disease
Krstic Dimitrije, Knuesel Irene, Deciphering the mechanism underyling late-onset Alzheimer's Disease, in Nature Reviews Neurology.
Impact of Prenatal Immune System Disturbances on Brain Development.
Madhusudan Amrita, Vogel Prisca, Knuesel Irene, Impact of Prenatal Immune System Disturbances on Brain Development., in Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacolog.
Reelin immunoreactivity in neuritic varicosities in the human hippocampal formation of non-demented and Alzheimer’s Disease patients
Notter Tina, Knuesel Irene, Reelin immunoreactivity in neuritic varicosities in the human hippocampal formation of non-demented and Alzheimer’s Disease patients, in Acta Neuropathologica Communicatons, in press..

Collaboration

Group / person Country
Types of collaboration
University of Texas Southwestern United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
University of South Florida United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Charité Universitätsmedizin Berlin Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
University of Amsterdam Netherlands (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Max Delbrück Center for Molecular Medicine Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Stanford School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
University of Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Spring Harbor Conference on Neurodegenerative Diseases 2012 28.11.2012 Cold Spring Harbor, NY, USA
Biotech-Forum 08.11.2012 Park Hyatt, Zurich
FENS Meeting 2012 14.07.2012 Barcelona, Spain
Giessbach Meeting 2012 03.05.2012 Giessbach, Brienz, Switzerland
Keystone Symposia: ApoE, Alzheimer's and Lipoprotein Biology (Q5) 26.02.2012 Keystone Resort, Keystone, Colorado, USA
AD Workshop 2011 – Fidelity Biosciences Research Initiative 15.06.2011 Kronberg, Germany
NCCR Neural plasticity and repair, Annual Meeting 2011 04.02.2011 Ittingen, Schweiz
Society for Neuroscience Annual Meeting 13.11.2010 San Diego, CA, USA


Self-organised

Title Date Place

Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Rethinking the Sequence of Cellular Events Leading to Alzheimer’s Disease Interview and Blog International 12.03.2013
New media (web, blogs, podcasts, news feeds etc.) Alzforum: Neuroinflammation – Prelude to Alzheimer’s? Webinar International 12.12.2012
Media relations: print media, online media Chronische Hirnentzündungen begünstigen Alzheimer Medienmitteilung der Universität Zürich German-speaking Switzerland 02.07.2012
Media relations: print media, online media Schwelbrand im Gehirn Sonntagszeitung German-speaking Switzerland 09.12.2012
Talks/events/exhibitions BrainFair Zurich: Auf Spuren- und Tätersuche: Aktuelles aus der Alzheimer Grundlagenforschung German-speaking Switzerland 17.03.2011
Video/Film NZZ Campus Neurowissenschaften German-speaking Switzerland 09.05.2011
Talks/events/exhibitions Volkshochschule Zürich: Ringvorlesung "Das plastische Gehirn: Form- und veränderbar?" German-speaking Switzerland 20.01.2011

Awards

Title Year
7th BioMed Central Research Award in Neuroscience, Neurology and Psychiatry 2013
Posterpreis SSPT Meeting 2012 2012

Associated projects

Number Title Start Funding scheme
144199 Do limbic seizures contribute to Alzheimer's disease-like pathology? Relevance of immune-mediated mechanisms 01.10.2012 Project funding
117806 The role of inflammatory modulators on Reelin-dependent signaling in the etiology of late-onset Alzheimer's disease 01.10.2007 Project funding

Abstract

A major advance in understanding the pathology underlying many neurological disorders has been the realization that inflammation represents a central factor in chronic and neurodegenerative conditions, including Alzheimer’s disease (AD). However, despite the growing number of studies linking neurotoxic inflammatory responses to AD pathogenesis, very little information is available on early, potentially causative inflammatory processes occurring at “pre-plaque deposition” stages, which might possess stronger disease-inducing and -modifying potential than the amyloid-beta plaque-associated inflammatory responses. Moreover, neurodegenerative diseases like AD are considered to have an adult onset. However, it is plausible that disturbances of normal development may significantly increase the brains’ susceptibility to neurodegenerative processes and other disease-specific changes, as shown for neurological disorders with a suggested developmental origin, like epilepsy or schizophrenia. So far, this putative relationship has not been investigated for neurodegenerative diseases. Instead, transgenic animals over-expressing rare AD-causing mutations have been widely used to investigate the role of genetic determinants on pathophysiological mechanisms of the disease. However, the majority of AD patients are sporadic late-onset cases with largely unknown etiology. Since aging is the major risk factor for late-onset AD, we have recently started to explore novel molecular pathways that might underlie the acceleration of aging-associated pathophysiological processes, potentially responsible for the shift from normal to pathological forms of aging. We focused our investigations on the molecular link between Reelin dysfunction and AD-related neuropathology. Reelin is a large extracellular protein essential for proper neuronal migration and cortical lamination during development. In adulthood, Reelin and its lipoprotein receptors are pivotal regulators of glutamatergic synapse function and plasticity and are involved in the control of Tau phosphorylation, amyloid precursor protein (APP) processing, as well as ApoE interactions with its receptors; thereby bringing together multiple AD-relevant signaling cascades. Our data collected so far has provided first evidence that Reelin itself forms amyloid-like plaques during normal aging and that these aggregates potentially reflect alterations in its proteolytic processing. This phenomenon is highly conserved since we detected it in aged rodents, non-human primates as well as postmortem human brain tissue. In mice, the neuropathological alterations significantly correlated with episodic-like memory deficits. Our findings also revealed that a prenatal exposure to the synthetic viral mimic polyriboinosinic-polyribocytidilic acid (PolyI:C) provokes a much earlier and higher accumulation of Reelin-positive plaques and even results in the formation of fibrillary amyloid-beta deposits that are associated with elevated levels of phosphorylated Tau protein and disrupted dendritic morphology in aged immune-challenged wild-type mice. These data provide the first evidence that a prenatal immune challenge is capable of inducing AD-like neuropathological hallmarks in aged wild type mice. Here, we aim to investigate the molecular mechanisms underlying the inflammation-induced dysfunctional Reelin signaling, the development of AD-like neuropathology and cognitive decline in mice. Specifically, we propose to determine the impact of pro-inflammatory cytokines on proteolytic cleavage of Reelin and its consequences on downstream signaling cascades involved in APP trafficking and amyloidogenic processing, as well as phosphorylation of Tau and neurofibrillary tangles formation. We will focus our investigations on the primary Reelin protease candidates: the ADAMTS family of metalloproteinases; since their expression levels are not only significantly upregulated in AD patients, but they are also elevated upon exposure to inflammatory cytokines, providing an exciting link between neuroinflammatory processes, Reelin cleavage, and AD pathophysiology. Finally, we will test the potential of anti-inflammatory drug therapy on protease activity and its impact on Reelin-dependent synaptic plasticity and cognitive performance in immune-challenged mice. The project identifies two parallel lines of research focusing on in vivo and in vitro experiments. They built on our implementation of prenatal brain infections in mice as a novel model of accelerated aging. The experiments will involve behavioural characterizations and pharmacological interventions, molecular biology techniques, biochemistry and proteomic analyses, complemented by immunohistochemical and -cytochemical investigations of transfected heterologuous cells and primary cultured hippocampal neurons exposed to different recombinant proteins, including Reelin and its proteolytic fragments, critical pro-inflammatory cytokines, proteases and their selective inhibitors.The proposed project comprises a focal and self-contained set of experiments with specific achievable aims. It will provide two excellent training opportunities in multi-disciplinary neuroscience research for a Postdoctoral fellow and a PhD student. The results generated are expected to represent a significant step towards an integrative approach to the significance of non-genetic animal models in general and the role of dysfunctional Reelin-mediated signaling in AD etiology in particular.
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