C9orf72 deficiency promotes microglial-mediated synaptic loss in aging and amyloid accumulation
| Autor: | Thomas E. Mahan, Deepti Lall, David M. Holtzman, Rita Sattler, A.K.M. Ghulam Muhammad, Michael Vazquez, Jesse Landeros, Daniel H. Geschwind, Hayk Davtyan, Ileana Lorenzini, Jacqueline G. O’Rourke, Jason D. Ulrich, Thomas A. Mota, Shaughn Bell, Junwon Kim, Jessica E. Rexach, Layla Ghaffari, Oksana Shelest, Mathew Blurton-Jones, Robert H. Baloh |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Aging amyotrophic lateral sclerosis Synaptic pruning microglia Neurodegenerative Alzheimer's Disease frontotemporal dementia Synapse Mice 0302 clinical medicine C9orf72 2.1 Biological and endogenous factors Psychology Aetiology Alzheimer's Disease Related Dementias (ADRD) DNA Repeat Expansion Microglia General Neuroscience Neurodegeneration neurodegeneration Frontotemporal Dementia (FTD) medicine.anatomical_structure Neurological Cognitive Sciences Alzheimer’s disease Amyloid Knockout Biology 03 medical and health sciences Rare Diseases medicine Genetics Acquired Cognitive Impairment Animals Neurology & Neurosurgery C9orf72 Protein Animal Neurosciences Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) medicine.disease Brain Disorders 030104 developmental biology Synapses Disease Models Dementia ALS Trinucleotide repeat expansion Lysosomes Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Neuron, vol 109, iss 14 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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