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03 12, 2021;4 (1): 329.

Maternal antibodies facilitate Amyloid-β clearance by activating Fc-receptor-Syk-mediated phagocytosis.

Tomer Illouz, Raneen Nicola, Linoy Ben-Shushan, Ravit Madar, Arya Biragyn, Eitan Okun
Author Information
  1. Tomer Illouz: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel. ORCID
  2. Raneen Nicola: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.
  3. Linoy Ben-Shushan: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel. ORCID
  4. Ravit Madar: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel.
  5. Arya Biragyn: Immunoregulation Section, Laboratory of Immunology and Molecular Biology, National Institute on Aging, Baltimore, MD, USA.
  6. Eitan Okun: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar-Ilan University, Ramat Gan, Israel. eitan.okun@biu.ac.il.
PMID: 33712740 DOI: 10.1038/s42003-021-01851-6

Abstract

Maternal antibodies (MAbs) protect against infections in immunologically-immature neonates. Maternally transferred immunity may also be harnessed to target diseases associated with endogenous protein misfolding and aggregation, such as Alzheimer's disease (AD) and AD-pathology in Down syndrome (DS). While familial early-onset AD (fEOAD) is associated with autosomal dominant mutations in the APP, PSEN1,2 genes, promoting cerebral Amyloid-β (Aβ) deposition, DS features a life-long overexpression of the APP and DYRK1A genes, leading to a cognitive decline mediated by Aβ overproduction and tau hyperphosphorylation. Although no prenatal screening for fEOAD-related mutations is in clinical practice, DS can be diagnosed in utero. We hypothesized that anti-Aβ MAbs might promote the removal of early Aβ accumulation in the central nervous system of human APP-expressing mice. To this end, a DNA-vaccine expressing Aβ was delivered to wild-type female mice, followed by mating with 5xFAD males, which exhibit early Aβ plaque formation. MAbs reduce the offspring's cortical Aβ levels 4 months after antibodies were undetectable, along with alleviating short-term memory deficits. MAbs elicit a long-term shift in microglial phenotype in a mechanism involving activation of the FcγR1/Syk/Cofilin pathway. These data suggest that maternal immunization can alleviate cognitive decline mediated by early Aβ deposition, as occurs in EOAD and DS.

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MeSH Term

Alzheimer Disease
Alzheimer Vaccines
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Animals
Antibodies
Behavior, Animal
Brain
Cognition
Disease Models, Animal
Female
Immunization
Male
Memory
Mice, Inbred C57BL
Mice, Transgenic
Microglia
Peptide Fragments
Phagocytosis
Phenotype
Plaque, Amyloid
Receptors, IgG
Signal Transduction
Syk Kinase
Vaccines, DNA
Mice

Chemicals

APP protein, human
Alzheimer Vaccines
Amyloid beta-Peptides
Amyloid beta-Protein Precursor
Antibodies
Fcgr1 protein, mouse
Peptide Fragments
Receptors, IgG
Vaccines, DNA
amyloid beta-protein (1-11)
Syk Kinase
Syk protein, mouse
Journal Article Research Support, N.I.H., Intramural
Article has an altmetric score of 16

Word Cloud

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