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

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Dibyadeep Datta ◽  
Shannon N. Leslie ◽  
Yury M. Morozov ◽  
Alvaro Duque ◽  
Pasko Rakic ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Rhesus Macaque ◽  
Protein Interactions ◽  
Dorsolateral Prefrontal Cortex ◽  
Rhesus Macaques ◽  
Inhibitory Synapses ◽  
Complement Cascade ◽  
Age Related ◽  
Dorsolateral Prefrontal ◽  
Age Related Changes

Abstract Background Cognitive 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. Methods Age-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. Results C1q 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. Conclusions These 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.

scholarly journals Age-Related Changes in the Rhesus Macaque Eye

2021 ◽  
Author(s):  
Kira Lin ◽  
Tu Tran ◽  
Soohyun Kim ◽  
Sangwan Park ◽  
Jiajia Chen ◽  
...  
Keyword(s):  
Optical Coherence Tomography ◽  
Intraocular Pressure ◽  
Rhesus Macaque ◽  
Axial Length ◽  
Rhesus Macaques ◽  
Anterior Segment ◽  
Optical Coherence ◽  
Lens Thickness ◽  
Age Related ◽  
Age Related Changes

Purpose: To assess age-related changes in the rhesus macaque eye and evaluate them to corresponding human age-related eye disease. Methods: Data from eye exams and imaging tests including intraocular pressure (IOP), lens thickness, axial length, and retinal optical coherence tomography (OCT) images were evaluated from 142 individuals and statistically analyzed for age-related changes. Quantitative autofluorescence (qAF) was measured as was the presence of macular lesions as related to age. Results: Ages of the 142 rhesus macaques ranged from 0.7 to 29 years (mean=16.4 years, stdev=7.5 years). Anterior segment measurements such as IOP, lens thickness, and axial length were acquired. Advanced retinal imaging in the form of optical coherence tomography and qAF were obtained. Quantitative assessments were made and variations by age groups were analyzed to compare with established age-related changes in human eyes. Quantitative analysis of data revealed age-related increase in intraocular pressure, ocular biometry (lens thickness and axial length), and presence of macular lesions. Age-related changes in thicknesses of retinal layers on OCT were observed and quantified. Age was correlated with increased qAF. Conclusions: The rhesus macaque has age-related ocular changes similar to humans. IOP increases with age while retinal ganglion cell layer thickness decreases. Macular lesions develop in some aged animals. Our findings support the concept that rhesus macaques may be useful for the study of important age-related diseases such as glaucoma, macular diseases, and cone disorders, and for development of therapies for these diseases.

scholarly journals Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Anita L. Pinner ◽  
Toni M. Mueller ◽  
Khaled Alganem ◽  
Robert McCullumsmith ◽  
James H. Meador-Woodruff
Keyword(s):  
Prefrontal Cortex ◽  
Protein Expression ◽  
Protein Interactions ◽  
Intracellular Signaling ◽  
Dorsolateral Prefrontal Cortex ◽  
Signaling Proteins ◽  
Protein Protein Interactions ◽  
Protein Prenylation ◽  
Lipid Modifications ◽  
Dorsolateral Prefrontal

AbstractThe pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein–protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated posttranslational lipid modifications may play a role in multiple neuropsychiatric disorders, including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that, in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (n = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine whether upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1 and prenylation-dependent processing enzymes RCE and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B, and RABGGTB in the cortex from rats treated long-term with haloperidol decanoate and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein–protein interactions and protein localization in schizophrenia.

scholarly journals Mapping Phosphodiesterase 4D (PDE4D) in Macaque Dorsolateral Prefrontal Cortex: Postsynaptic Compartmentalization in Layer III Pyramidal Cell Circuits

2020 ◽  
Vol 14 ◽  
Author(s):  
Dibyadeep Datta ◽  
John F. Enwright ◽  
Dominique Arion ◽  
Constantinos D. Paspalas ◽  
Yury M. Morozov ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Dorsolateral Prefrontal Cortex ◽  
Calcium Release ◽  
Smooth Endoplasmic Reticulum ◽  
Rhesus Macaques ◽  
Pyramidal Cells ◽  
Camp Signaling ◽  
Association Cortex ◽  
Axon Terminals ◽  
Dorsolateral Prefrontal

cAMP signaling has powerful, negative effects on cognitive functions of the primate dorsolateral prefrontal cortex (dlPFC), opening potassium channels to reduce firing and impair working memory, and increasing tau phosphorylation in aging neurons. This contrasts with cAMP actions in classic circuits, where it enhances plasticity and transmitter release. PDE4 isozymes regulate cAMP actions, and thus have been a focus of research and drug discovery. Previous work has focused on the localization of PDE4A and PDE4B in dlPFC, but PDE4D is also of great interest, as it is the predominant PDE4 isoform in primate association cortex, and PDE4D expression decreases with aging in human dlPFC. Here we used laser-capture microdissection transcriptomics and found that PDE4D message is enriched in pyramidal cells compared to GABAergic PV-interneurons in layer III of the human dlPFC. A parallel study in rhesus macaques using high-spatial resolution immunoelectron microscopy revealed the ultrastructural locations of PDE4D in primate dlPFC with clarity not possible in human post-mortem tissue. PDE4D was especially prominent in dendrites associated with microtubules, mitochondria, and likely smooth endoplasmic reticulum (SER). There was substantial postsynaptic labeling in dendritic spines, associated with the SER spine-apparatus near glutamatergic-like axospinous synapses, but sparse labeling in axon terminals. We also observed dense PDE4D labeling perisynaptically in astroglial leaflets ensheathing glutamatergic connections. These data suggest that PDE4D is strategically positioned to regulate cAMP signaling in dlPFC glutamatergic synapses and circuits, especially in postsynaptic compartments where it is localized to influence cAMP actions on intracellular trafficking, mitochondrial physiology, and internal calcium release.

scholarly journals Protein expression of prenyltransferase subunits in postmortem schizophrenia dorsolateral prefrontal cortex

2019 ◽  
Author(s):  
Anita L. Pinner ◽  
Toni M. Mueller ◽  
Khaled Alganem ◽  
Robert McCullumsmith ◽  
James H. Meador-Woodruff
Keyword(s):  
Prefrontal Cortex ◽  
Protein Expression ◽  
Protein Interactions ◽  
Intracellular Signaling ◽  
Dorsolateral Prefrontal Cortex ◽  
Signaling Proteins ◽  
Protein Protein Interactions ◽  
Protein Prenylation ◽  
Lipid Modifications ◽  
Dorsolateral Prefrontal

AbstractThe pathophysiology of schizophrenia includes altered neurotransmission, dysregulated intracellular signaling pathway activity, and abnormal dendritic morphology that contribute to deficits of synaptic plasticity in the disorder. These processes all require dynamic protein-protein interactions at cell membranes. Lipid modifications target proteins to membranes by increasing substrate hydrophobicity by the addition of a fatty acid or isoprenyl moiety, and recent evidence suggests that dysregulated post-translational lipid modifications may play a role in multiple neuropsychiatric disorders including schizophrenia. Consistent with these emerging findings, we have recently reported decreased protein S-palmitoylation in schizophrenia. Protein prenylation is a lipid modification that occurs upstream of S-palmitoylation on many protein substrates, facilitating membrane localization and activity of key intracellular signaling proteins. Accordingly, we hypothesized that in addition to palmitoylation, protein prenylation may be abnormal in schizophrenia. To test this, we assayed protein expression of the five prenyltransferase subunits (FNTA, FNTB, PGGT1B, RABGGTA, and RABGGTB) in postmortem dorsolateral prefrontal cortex from patients with schizophrenia and paired comparison subjects (N = 13 pairs). We found decreased levels of FNTA (14%), PGGT1B (13%), and RABGGTB (8%) in schizophrenia. To determine if upstream or downstream factors may be driving these changes, we also assayed protein expression of the isoprenoid synthases FDPS and GGPS1, and prenylation-dependent processing enzymes REC and ICMT. We found these upstream and downstream enzymes to have normal protein expression. To rule out effects from chronic antipsychotic treatment, we assayed FNTA, PGGT1B and RABGGTB in cortex from rats treated long-term with haloperidol decanoate, and found no change in the expression of these proteins. Given the role prenylation plays in localization of key signaling proteins found at the synapse, these data offer a potential mechanism underlying abnormal protein-protein interactions and protein localization in schizophrenia.

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