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Classical complement cascade initiating C1q protein within neurons in the aged rhesus macaque dorsolateral prefrontal cortex

Authors
  • Datta, Dibyadeep1
  • Leslie, Shannon N.2, 2
  • Morozov, Yury M.1
  • Duque, Alvaro1
  • Rakic, Pasko1
  • van Dyck, Christopher H.1, 2
  • Nairn, Angus C.2
  • Arnsten, Amy F. T.1
  • 1 Yale University School of Medicine, 333 Cedar St., New Haven, CT, 06511, USA , New Haven (United States)
  • 2 Yale University School of Medicine, New Haven, USA , New Haven (United States)
Type
Published Article
Journal
Journal of Neuroinflammation
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jan 06, 2020
Volume
17
Issue
1
Identifiers
DOI: 10.1186/s12974-019-1683-1
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundCognitive impairment in schizophrenia, aging, and Alzheimer’s disease is associated with spine and synapse loss from the dorsolateral prefrontal cortex (dlPFC) layer III. Complement cascade signaling is critical in driving spine loss and disease pathogenesis. Complement signaling is initiated by C1q, which tags synapses for elimination. C1q is thought to be expressed predominately by microglia, but its expression in primate dlPFC has never been examined. The current study assayed C1q levels in aging primate dlPFC and rat medial PFC (mPFC) and used immunoelectron microscopy (immunoEM), immunoblotting, and co-immunoprecipitation (co-IP) to reveal the precise anatomical distribution and interactions of C1q.MethodsAge-related changes in C1q levels in rhesus macaque dlPFC and rat mPFC were examined using immunoblotting. High-spatial resolution immunoEM was used to interrogate the subcellular localization of C1q in aged macaque layer III dlPFC and aged rat layer III mPFC. co-IP techniques quantified protein-protein interactions for C1q and proteins associated with excitatory and inhibitory synapses in macaque dlPFC.ResultsC1q levels were markedly increased in the aged macaque dlPFC. Ultrastructural localization found the expected C1q localization in glia, including those ensheathing synapses, but also revealed extensive localization within neurons. C1q was found near synapses, within terminals and in spines, but was also observed in dendrites, often near abnormal mitochondria. Similar analyses in aging rat mPFC corroborated the findings in rhesus macaques. C1q protein increasingly associated with PSD95 with age in macaque, consistent with its synaptic localization as evidenced by EM.ConclusionsThese findings reveal novel, intra-neuronal distribution patterns for C1q in the aging primate cortex, including evidence of C1q in dendrites. They suggest that age-related changes in the dlPFC may increase C1q expression and synaptic tagging for glial phagocytosis, a possible mechanism for age-related degeneration.

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