Restoring microglial and astroglial homeostasis using DNA immunization in a down Syndrome mouse model.

Illouz, Tomer; Madar, Ravit; Biragyn, Arya; Okun, Eitan

doi:10.1016/j.bbi.2018.10.004

Cited by 22Alzheimer's disease research and treatmentsDown syndrome and intellectual disability researchNeuroinflammation and Neurodegeneration Mechanisms

Restoring microglial and astroglial homeostasis using DNA immunization in a down Syndrome mouse model.

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Illouz, Tomer, Madar, Ravit, Biragyn, Arya, Okun, Eitan·2019·Brain, Behavior, and Immunity

DOI 10.1016/j.bbi.2018.10.004PMC PMC6358279

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Abstract

Down Syndrome (DS), the most common cause of genetic intellectual disability, is characterized by over-expression of the APP and DYRK1A genes, located on the triplicated chromosome 21. This chromosomal abnormality leads to a cognitive decline mediated by Amyloid-β (Aβ) overproduction and tau hyper-phosphorylation as early as the age of 40. In this study, we used the Ts65Dn mouse model of DS to evaluate the beneficial effect of a DNA vaccination against the Aβ1-11 fragment, in ameliorating Aβ-related neuropathology and rescue of cognitive and behavioral abilities. Anti-Aβ1-11 vaccination induced antibody production and facilitated clearance of soluble oligomers and small extracellular inclusions of Aβ from the hippocampus and cortex of Ts65Dn mice. This was correlated with reduced neurodegeneration and restoration of the homeostatic phenotype of microglial and astroglial cells. Vaccinated Ts65Dn mice performed better in spatial-learning tasks, exhibited reduced motor hyperactivity typical for this strain, and restored short-term memory abilities. Our findings support the hypothesis that DS individuals may benefit from active immunotherapy against Aβ from a young age by slowing the progression of dementia.

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Human studies suggest increased microglia activation in DS, and Ts65Dn appears to recapitulate this.
“There have been few studies of microglia in humans and the results are inconsistent but suggest increased activation, a phenotype that Ts65Dn also appears to recapitulate (Illouz et al., 2019).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Illouz et al., 2019
The Introduction (page unavailable) reports elevated microglial activation markers in human Down syndrome specimens. The Results section on microglial phenotype (page unavailable) finds signs of activation in sham-treated Ts65Dn mice, but similar signs also appear in wild-type mice; it does not establish that Ts65Dn has greater activation than wild type. Thus the proposed recapitulation is only partly supported. (LLM, conf=0.82)
Experimental — accuracy not yet measured
In Ts65Dn, there is an increase in astrocytes (S100β) in both cortex and hippocampus.
“Additionally, an increase in astrocytes as identified by S100β staining has been found in both the cortex and the hippocampus (Illouz et al., 2019).”
From Neurodevelopment in Down syndrome: Concordance in humans and models (2022) · cites this paper as Illouz et al., 2019

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APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome
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Down syndrome individuals with Alzheimer's disease have a distinct neuroinflammatory phenotype compared to sporadic Alzheimer's disease
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Enlarged Brain Ventricles and Impaired Neurogenesis in the Ts1Cje and Ts2Cje Mouse Models of Down Syndrome
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Histological Staining of Amyloid and Pre-amyloid Peptides and Proteins in Mouse Tissue
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S100B and APP Promote a Gliocentric Shift and Impaired Neurogenesis in Down Syndrome Neural Progenitors
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Memantine Normalizes Several Phenotypic Features in the Ts65Dn Mouse Model of Down Syndrome
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Alteration of inhibitory circuits in the somatosensory cortex of Ts65Dn mice, a model for down’s syndrome.
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Lithium Restores Neurogenesis in the Subventricular Zone of the Ts65Dn Mouse, a Model for Down Syndrome
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WIS‐neuromath enables versatile high throughput analyses of neuronal processes
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Differential effects of trisomy on brain shape and volume in related aneuploid mouse models
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Neurological changes and emotional functioning in adults with Down Syndrome
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Lowering β-Amyloid Levels Rescues Learning and Memory in a Down Syndrome Mouse Model
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Age-Related Neurodegeneration and Memory Loss in Down Syndrome
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Astrocytes: a cellular player in Aβ clearance and degradation
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Effects of voluntary physical exercise on adult hippocampal neurogenesis and behavior of Ts65Dn mice, a model of Down syndrome
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CD11b-mediated migratory property of peripheral blood B cells
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The Place of Choline Acetyltransferase Activity Measurement in the “Cholinergic Hypothesis” of Neurodegenerative Diseases
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Neurobiological Elements of Cognitive Dysfunction in Down Syndrome: Exploring the Role of APP
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Cell proliferation is reduced in the dentate gyrus of aged but not young Ts65Dn mice, a model of Down syndrome
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Unraveling cognitive traits using the Morris water maze unbiased strategy classification (MUST-C) algorithm
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Maturation of Recombinant Hepatitis B Virus Surface Antigen Particles
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Three‐dimensional synaptic ultrastructure in the dentate gyrus and hippocampal area CA3 in the Ts65Dn mouse model of down syndrome
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Episodic-like memory in Ts65Dn, a mouse model of Down syndrome
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Naturally occurring autoantibodies against beta-amyloid: investigating their role in transgenic animal and in vitro models of Alzheimer's disease
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Down's syndrome astrocytes have greater antioxidant capacity than euploid astrocytes
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DNA immunization with HBsAg-based particles expressing a B cell epitope of amyloid β-peptide attenuates disease progression and prolongs survival in a mouse model of Alzheimer's disease
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β-Amyloid overload does not directly correlate with SAPK/JNK activation and tau protein phosphorylation in the cerebellar cortex of Ts65Dn mice
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Mouse models of Down syndrome
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Microglial depletion prevents extracellular matrix changes and striatal volume reduction in a model of Huntington's disease
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Rescuing Over-activated Microglia Restores Cognitive Performance in Juvenile Animals of the Dp(16) Mouse Model of down Syndrome.
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Klein, J. A., & Haydar, T. F. (2022) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2022.941855 · Cited by 47 · see citing works
“Additionally, an increase in astrocytes as identified by S100β staining has been found in both the cortex and the hippocampus (Illouz et al., 2019).”
Background
Translational validity and implications of pharmacotherapies in preclinical models of Down syndrome
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Astroglial and microglial pathology in Down syndrome: Focus on Alzheimer's disease
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Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis
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Down’s syndrome and COVID-19: risk or protection factor against infection? A molecular and genetic approach
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Inhibitory designer receptors aggravate memory loss in a mouse model of down syndrome
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Induction of an effective anti-Amyloid-β humoral response in aged mice
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Sustained microglial activation and accelerated elimination of dendritic spines during acute sleep deprivation and restoration
Liu, J., Xu, Y., Ji, Y., Li, K., Wang, S., Zhao, B., Ruan, J., Foulkes, N. S., Zhang, S., & Zhao, H. (2023) · The Innovation Life · doi:10.59717/j.xinn-life.2023.100037 · Cited by 8 · see citing works
Beyond Quiescent and Active: Intermediate Microglial Transcriptomic States in a Mouse Model of Down Syndrome
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TMEM106B Puncta Is Increased in Multiple Sclerosis Plaques, and Reduced Protein in Mice Results in Delayed Lipid Clearance Following CNS Injury
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Renovating the Barnes maze for mouse models of dementia with STARR FIELD: A 4-day protocol for learning rate, retention, and cognitive flexibility
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Using mouse models to understand Alzheimer's disease mechanisms in the context of trisomy of chromosome 21
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Astrocytopathy Is Associated with CA1 Synaptic Dysfunction in a Mouse Model of Down Syndrome
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Targeting dysregulated CB1 receptors in a Down syndrome mouse model improves neurological outcomes
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Down Syndrome: Progress in Defining Pathogenesis and Treatments for Neurodevelopmental Deficits and Alzheimer’s Disease
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Belichenko, P., Madani, R., Rey-Bellet, L., Pihlgren, M., Becker, A., Plassard, A., Vuillermot, S., Giriens, V., Nosheny, R., Kleschevnikov, A., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0152471 · Cited by 35 · see citing works
Active Immunization with DNA Vaccine Reduced Cerebral Inflammation and Improved Cognitive Ability in APP/PS1 Transgenic Mice by In Vivo Electroporation
Xing, X., Sha, S., Chen, X.-H., Guo, W., Guo, R., Jiang, T., & Cao, Y. (2015) · Neurochemical Research · doi:10.1007/s11064-015-1559-4 · Cited by 5 · see citing works
Experience-dependent reduction of soluble β-amyloid oligomers and rescue of cognitive abilities in middle-age Ts65Dn mice, a model of Down syndrome
Sansevero, G., Begenisic, T., Mainardi, M., & Sale, A. (2016) · Experimental Neurology · doi:10.1016/j.expneurol.2016.06.006 · Cited by 29 · see citing works
Changes in the brain transcriptome after DNA Aβ42 trimer immunization in a 3xTg-AD mouse model
Lambracht‐Washington, D., Fu, M., Hynan, L. S., & Rosenberg, R. N. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.105221 · Cited by 27 · see citing works
Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis
Illouz, T., Nicola, R., Ben-Shushan, L., Madar, R., Biragyn, A., & Okun, E. (2021) · Communications Biology · doi:10.1038/s42003-021-01851-6 · Cited by 21 · see citing works
Self-citation

Authors: Illouz, T., Madar, R., Biragyn, A., & Okun, E.
Affiliations: Bar-Ilan University (IL)
National Institutes of Health (US)
Corresponding author: Okun, Eitan
ORCID: Illouz, Tomer
Madar, Ravit
Biragyn, Arya
Okun, Eitan
Venue: Brain, Behavior, and Immunity
Publisher: Elsevier BV
Published: 2019-01
Volume: 75
Pages: 163-180
ISSN: 0889-1591 (ISSN-L)
DOI: 10.1016/j.bbi.2018.10.004
PMC: PMC6358279
OpenAlex: W2898109603
Cited by: 22
References: 146
Citations by year: 2026: 1 · 2025: 3 · 2024: 1 · 2023: 3 · 2022: 3 · 2021: 3 · 2020: 4 · 2019: 4
FWCI: 1.89
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Brain Behavior and Immunity (publishedVersion, cc-by)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion, other-oa)
PubMed Central (acceptedVersion, cc-by)
Funders: Alzheimer's Association
National Institutes of Health (Z99 AG999999)
National Institute on Aging (Z01AG000444)
Topics: Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords: Down syndrome, Ts65Dn mouse model, DNA vaccine, amyloid-beta, active immunotherapy, microglial homeostasis, APP, DYRK1A, amyloid-beta oligomers, neurodegeneration, cognitive impairment, spatial learning, short-term memory, motor hyperactivity, Alzheimer's disease
MeSH terms: Dyrk Kinases, Alzheimer Disease, Animals, Astrocytes, Brain, Disease Models, Animal, DNA, Down Syndrome, Hippocampus, Immunization, Male, Mice, Transgenic, Phenotype, Phosphorylation, Protein-Tyrosine Kinases, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Protein Serine-Threonine Kinases, Microglia, Mice

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Restoring microglial and astroglial homeostasis using DNA immunization in a down Syndrome mouse model.

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