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Published on: December 26, 2016
Immune proteins C1q and CD47 may contribute to aberrant microglia-mediated synapse loss in the aging monkey brain
Sarah A DeVries1, Bryce Conner2, Christina Dimovasili2
1Laboratory for Cognitive Neurobiology, Department of Anatomy & Neurobiology, Boston University Chobanian & Avedisian School of Medicine, Boston University Medical Campus, Boston, MA, USA. sdevries@bu.edu.
Abstract:
Cognitive impairment in learning, memory, and executive function occurs in normal aging even in the absence of Alzheimer's disease (AD). While neurons do not degenerate in humans or monkeys free of AD, there are structural changes including synapse loss and dendritic atrophy, especially in the dorsolateral prefrontal cortex (dlPFC), and these correlate with cognitive age-related impairment. Developmental studies revealed activity-dependent neuronal properties that lead to synapse remodeling by microglia. Microglia-mediated phagocytosis that may eliminate synapses is regulated by immune "eat me" and "don't eat me" signaling proteins in an activity-dependent manner, so that less active synapses are eliminated. Whether this process contributes to age-related synapse loss remains unknown. The present study used a rhesus monkey model of normal aging to investigate the balance between the "eat me" signal, complement component C1q, and the "don't eat me" signal, transmembrane glycoprotein CD47, relative to age-related synapse loss in dlPFC Area 46. Results showed an age-related elevation of C1q and reduction of CD47 at PSD95+ synapses that is associated with cognitive impairment. Additionally, reduced neuronal CD47 RNA expression was found, indicating that aged neurons were less able to produce the protective signal CD47. Interestingly, microglia do not show the hypertrophic morphology indicative of phagocytic activity. These findings suggest that in the aging brain, changes in the balance of immunologic proteins give microglia instructions favoring synapse elimination of less active synapses, but this may occur by a process other than classic phagocytosis such as trogocytosis.
Insights
Normal aging impairs cognition through synapse loss in the brain. In aged monkeys, altered immune signals (C1q, CD47) at synapses correlate with cognitive decline, suggesting a role in age-related memory loss.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Normal aging, distinct from Alzheimer's disease, causes cognitive decline.
- This decline is linked to structural brain changes like synapse loss in the dorsolateral prefrontal cortex (dlPFC).
- Microglia, immune cells in the brain, remodel synapses based on neuronal activity, potentially eliminating less active ones.
Purpose of the Study:
- To investigate the role of immune "eat me" (C1q) and "don't eat me" (CD47) signals in age-related synapse loss.
- To examine the balance of these signals in the dlPFC of normally aging rhesus monkeys.
- To correlate these molecular changes with cognitive function.
Main Methods:
- Utilized a rhesus monkey model of normal aging.
- Analyzed the expression of C1q and CD47 at synapses in dlPFC Area 46.
- Assessed neuronal CD47 RNA expression.
- Examined microglial morphology for signs of phagocytic activity.
Main Results:
- Aged synapses showed increased C1q ("eat me") and decreased CD47 ("don't eat me") signals.
- Reduced neuronal CD47 RNA expression was observed in aged neurons.
- Cognitive impairment in aged monkeys correlated with these synaptic changes.
- Microglia did not display morphology indicative of active phagocytosis.
Conclusions:
- Altered balance of immune signals (C1q, CD47) at synapses contributes to age-related synapse loss.
- Aged neurons may reduce CD47 production, making synapses more vulnerable to elimination.
- Synapse elimination in aging may occur via mechanisms other than classical phagocytosis, such as trogocytosis.
