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C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
Deepti Lall1, Ileana Lorenzini2, Thomas A Mota1
1Center for Neural Science and Medicine, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
Abstract:
C9orf72 repeat expansions cause inherited amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD) and result in both loss of C9orf72 protein expression and production of potentially toxic RNA and dipeptide repeat proteins. In addition to ALS/FTD, C9orf72 repeat expansions have been reported in a broad array of neurodegenerative syndromes, including Alzheimer's disease. Here we show that C9orf72 deficiency promotes a change in the homeostatic signature in microglia and a transition to an inflammatory state characterized by an enhanced type I IFN signature. Furthermore, C9orf72-depleted microglia trigger age-dependent neuronal defects, in particular enhanced cortical synaptic pruning, leading to altered learning and memory behaviors in mice. Interestingly, C9orf72-deficient microglia promote enhanced synapse loss and neuronal deficits in a mouse model of amyloid accumulation while paradoxically improving plaque clearance. These findings suggest that altered microglial function due to decreased C9orf72 expression directly contributes to neurodegeneration in repeat expansion carriers independent of gain-of-function toxicities.
Insights
C9orf72 repeat expansions cause neurodegenerative diseases like ALS/FTD. Reduced C9orf72 protein in microglia drives inflammation and neuronal defects, impacting learning and memory.
Area of Science:
- Neuroscience
- Genetics
- Immunology
Background:
- C9orf72 repeat expansions are a primary genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD).
- These expansions lead to both loss of C9orf72 protein and production of toxic RNA and dipeptide repeat proteins.
- C9orf72 repeat expansions are also implicated in other neurodegenerative conditions, including Alzheimer's disease.
Purpose of the Study:
- To investigate the functional consequences of C9orf72 deficiency in microglia.
- To determine how C9orf72-deficient microglia affect neuronal health and behavior.
- To explore the role of C9orf72 in the context of amyloid pathology.
Main Methods:
- Utilized mouse models with C9orf72 deficiency.
- Analyzed microglial homeostatic and inflammatory signatures, including type I interferon response.
- Assessed age-dependent neuronal defects, synaptic pruning, and learning/memory behaviors.
- Examined C9orf72-deficient microglia in a mouse model of amyloid accumulation.
Main Results:
- C9orf72 deficiency alters microglial homeostatic signatures, promoting a pro-inflammatory state with an enhanced type I interferon response.
- Microglia lacking C9orf72 induce age-dependent neuronal deficits, specifically increased cortical synaptic pruning, leading to impaired learning and memory in mice.
- In an amyloid accumulation model, C9orf72-deficient microglia exacerbate synapse loss and neuronal deficits but paradoxically enhance amyloid plaque clearance.
Conclusions:
- Decreased C9orf72 expression in microglia directly contributes to neurodegeneration.
- Altered microglial function, driven by C9orf72 deficiency, plays a role in the pathogenesis of repeat expansion disorders.
- These findings suggest a mechanism independent of toxic gain-of-function effects in C9orf72-related neurodegeneration.
