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Cited by 49Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammatory mediators and NSAID effects

DOCK2 Is a Microglial Specific Regulator of Central Nervous System Innate Immunity Found in Normal and Alzheimer’s Disease Brain

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Cimino, Patrick J., Sokal, Izabela, Leverenz, James, Fukui, Yoshinori, Montine, Thomas J.·2009·The American Journal of Pathology
DOI 10.2353/ajpath.2009.090443PMC PMC2751558
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Abstract

Neuroinflammation is a hallmark of several neurodegenerative diseases, including Alzheimer's disease (AD). Strong epidemiological and experimental evidence supports the use of nonsteroidal anti-inflammatory drugs to reduce AD risk. However, poor outcome in clinical trials and toxicity in a prevention trial have shifted focus away from these cyclooxygenase (COX) inhibitors to seek additional therapeutic targets in the prostaglandin pathway. Previously, the prostaglandin E2 receptor, EP2, was shown to regulate neuroinflammation and reduce Abeta plaque burden in transgenic mice. Unfortunately, widespread EP2 distribution and a direct effect on COX2 induction make EP2 a less desirable target. In this study, we link dedicator of cytokinesis 2 (DOCK2) to the prostaglandin pathway in the brain. Additionally, we show that DOCK2 regulates microglial innate immunity independent of COX2 induction and that DOCK2+ microglia are associated with human AD pathology. Together, these results suggest DOCK2 as a COX2 expression-independent therapeutic target for neurodegenerative diseases such as AD.

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  • DOCK2 has been implicated in the pathogenesis of Alzheimer's disease by enhancing amyloid beta plaque formation.

    “It has been implicated in the pathogenesis of AD by enhancing amyloid beta (Aβ) plaque formation (66, 67).”

    From RHO to the DOCK for GDP disembarking: Structural insights into the DOCK GTPase nucleotide exchange factors (2021) · cites this paper as [66]

    The ‘DOCK2 in Normal and AD Human Brain’ section reports that DOCK2-positive microglia are associated with amyloid-beta plaques, supporting a link to Alzheimer’s pathology. It does not show that DOCK2 enhances plaque formation; the Discussion instead describes plaques as recruiting microglia and says DOCK2 is unlikely to mediate the phagocytic suppression discussed there. Page numbers were not available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Cimino, P. J., Sokal, I., Leverenz, J., Fukui, Y., & Montine, T. J.
Affiliations
  • University of Washington (US)
  • Kyushu University (JP)
Corresponding author
Cimino, Patrick J.
ORCID
Venue
The American Journal of Pathology
Publisher
Elsevier BV
Published
2009-10
Volume
175
Issue
4
Pages
1622-1630
ISSN
0002-9440 (ISSN-L)
DOI
10.2353/ajpath.2009.090443
PMC
PMC2751558
OpenAlex
W1971000103
Cited by
49
References
11
Citations by year
2026: 2 · 2025: 1 · 2024: 5 · 2023: 2 · 2022: 5 · 2021: 4 · 2020: 4 · 2018: 5 · 2017: 4 · 2016: 3 · 2015: 1 · 2014: 4 · 2013: 2 · 2012: 2
FWCI
1.43
Type
journal article
Language
en
Open access
Licence
Locations
  • American Journal Of Pathology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institutes of Health (AG05136, AG13280, AG24011, GM007266)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Pharmacology › Inflammatory mediators and NSAID effects
Keywords
DOCK2, microglia, Alzheimer's disease, neuroinflammation, innate immunity, prostaglandin pathway, therapeutic target, neurodegenerative diseases
MeSH terms
Alzheimer Disease, Animals, Brain, Gene Expression Regulation, Humans, Immunity, Innate, Mice, Inbred C57BL, Organ Specificity, RNA, Messenger, Microglia, Receptors, Prostaglandin E, Guanine Nucleotide Exchange Factors, GTPase-Activating Proteins, Protein Transport, Mice, Cyclooxygenase 2, Receptors, Prostaglandin E, EP2 Subtype

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