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Cited by 36Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsNeurological Disease Mechanisms and Treatments

Ablation of the microglial protein DOCK2 reduces amyloid burden in a mouse model of Alzheimer's disease

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Cimino, Patrick J., Yang, Yue, Li, Xianwu, Hemingway, Jake F., Cherne, Makenzie K., Khademi, Shawn B., Fukui, Yoshinori, Montine, Kathleen S. +2 more·2013·Experimental and Molecular Pathology
DOI 10.1016/j.yexmp.2013.01.002PMC PMC3602334
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Abstract

Alzheimer's disease (AD) neuropathology is characterized by innate immune activation primarily through prostaglandin E2 (PGE2) signaling. Dedicator of cytokinesis 2 (DOCK2) is a guanyl nucleotide exchange factor expressed exclusively in microglia in the brain and is regulated by PGE2 receptor EP2. DOCK2 modulates microglia cytokine secretion, phagocytosis, and paracrine neurotoxicity. EP2 ablation in experimental AD results in reduced oxidative damage and amyloid beta (Aβ) burden. This discovery led us to hypothesize that genetic ablation of DOCK2 would replicate the anti-Aβ effects of loss of EP2 in experimental AD. To test this hypothesis, we crossed mice that lacked DOCK2 (DOCK2-/-), were hemizygous for DOCK2 (DOCK2+/-), or that expressed two DOCK2 genes (DOCK2+/+) with APPswe-PS1Δe9 mice (a model of AD). While we found no DOCK2-dependent differences in cortex or in hippocampal microglia density or morphology in APPswe-PS1Δe9 mice, cerebral cortical and hippocampal Aβ plaque area and size were significantly reduced in 10-month-old APPswe-PS1Δe9/DOCK2-/- mice compared with APPswe-PS1Δe9/DOCK2+/+ controls. DOCK2 hemizygous APPswe-PS1Δe9 mice had intermediate Aβ plaque levels. Interestingly, soluble Aβ42 was not significantly different among the three genotypes, suggesting the effects were mediated specifically in fibrillar Aβ. In combination with earlier cell culture results, our in vivo results presented here suggest DOCK2 contributes to Aβ plaque burden via regulation of microglial innate immune function and may represent a novel therapeutic target for AD.

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Authors
Cimino, P. J., Yang, Y., Li, X., Hemingway, J. F., Cherne, M. K., Khademi, S. B., Fukui, Y., Montine, K. S., Montine, T. J., & Keene, C. D.
Affiliations
  • University of Washington (US)
  • Kyushu University (JP)
Corresponding author
Cimino, Patrick J.
ORCID
Venue
Experimental and Molecular Pathology
Publisher
Elsevier BV
Published
2013-04
Volume
94
Issue
2
Pages
366-371
ISSN
0014-4800 (ISSN-L)
DOI
10.1016/j.yexmp.2013.01.002
PMC
PMC3602334
OpenAlex
W1994292998
Cited by
36
References
49
Citations by year
2026: 2 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 1 · 2019: 1 · 2017: 1 · 2016: 2 · 2015: 2 · 2014: 4 · 2013: 3
FWCI
2.55
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Experimental and Molecular Pathology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Nancy and Buster Alvord Endowment
  • Japan Society for the Promotion of Science (25251015, 24111001, 22247017)
  • National Institute on Aging (P50 AG05136, F30AG030914, P50AG005136)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords
DOCK2, Alzheimer's disease, amyloid plaques, microglia, EP2 receptor, prostaglandin E2 signaling, innate immunity, APPswe/PS1ΔE9 mice, fibrillar amyloid-beta, therapeutic target
MeSH terms
Alzheimer Disease, Animals, Brain, Disease Models, Animal, Genotype, Immunity, Innate, Mice, Inbred C57BL, Dinoprostone, Amyloid beta-Peptides, Mice, Knockout, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, Mice, Plaque, Amyloid

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