C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease
IntroductionSynaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and...
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ftcdlib:oai:escholarship.org:ark:/13030/qt68p1f01h 2024-05-12T08:00:20+00:00 C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease Gomez‐Arboledas, Angela Fonseca, Maria I Kramar, Enikö Chu, Shu‐Hui Schartz, Nicole D Selvan, Purnika Wood, Marcelo A Tenner, Andrea J 2173 - 2190 2024-03-01 application/pdf https://escholarship.org/uc/item/68p1f01h unknown eScholarship, University of California qt68p1f01h https://escholarship.org/uc/item/68p1f01h public Alzheimer's & Dementia, vol 20, iss 3 Biomedical and Clinical Sciences Neurosciences Clinical Sciences Dementia Acquired Cognitive Impairment Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Genetics Aging Brain Disorders Alzheimer's Disease Neurodegenerative 2.1 Biological and endogenous factors Aetiology Neurological Mice Animals Humans Alzheimer Disease Synapses Long-Term Potentiation Disease Models Animal C1q C5aR1 LTP microglia synaptic pruning Geriatrics Biological psychology article 2024 ftcdlib 2024-04-17T14:06:41Z IntroductionSynaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.MethodsA combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD.ResultsGenetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP).DiscussionReduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.HighlightsC5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease. Article in Journal/Newspaper Arctic University of California: eScholarship Arctic |
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University of California: eScholarship |
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language |
unknown |
topic |
Biomedical and Clinical Sciences Neurosciences Clinical Sciences Dementia Acquired Cognitive Impairment Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Genetics Aging Brain Disorders Alzheimer's Disease Neurodegenerative 2.1 Biological and endogenous factors Aetiology Neurological Mice Animals Humans Alzheimer Disease Synapses Long-Term Potentiation Disease Models Animal C1q C5aR1 LTP microglia synaptic pruning Geriatrics Biological psychology |
spellingShingle |
Biomedical and Clinical Sciences Neurosciences Clinical Sciences Dementia Acquired Cognitive Impairment Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Genetics Aging Brain Disorders Alzheimer's Disease Neurodegenerative 2.1 Biological and endogenous factors Aetiology Neurological Mice Animals Humans Alzheimer Disease Synapses Long-Term Potentiation Disease Models Animal C1q C5aR1 LTP microglia synaptic pruning Geriatrics Biological psychology Gomez‐Arboledas, Angela Fonseca, Maria I Kramar, Enikö Chu, Shu‐Hui Schartz, Nicole D Selvan, Purnika Wood, Marcelo A Tenner, Andrea J C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
topic_facet |
Biomedical and Clinical Sciences Neurosciences Clinical Sciences Dementia Acquired Cognitive Impairment Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) Genetics Aging Brain Disorders Alzheimer's Disease Neurodegenerative 2.1 Biological and endogenous factors Aetiology Neurological Mice Animals Humans Alzheimer Disease Synapses Long-Term Potentiation Disease Models Animal C1q C5aR1 LTP microglia synaptic pruning Geriatrics Biological psychology |
description |
IntroductionSynaptic loss is a hallmark of Alzheimer's disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD.MethodsA combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD.ResultsGenetic ablation or pharmacological inhibition of C5aR1 partially rescues excessive pre-synaptic pruning and synaptic loss in an age and region-dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP).DiscussionReduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.HighlightsC5aR1 ablation restores long-term potentiation in the Arctic model of AD. C5aR1 ablation rescues region specific excessive pre-synaptic loss. C5aR1 antagonist, PMX205, rescues VGlut1 loss in the Tg2576 model of AD. C1q tagging is not sufficient to induce VGlut1 microglial ingestion. Astrocytes contribute to excessive pre-synaptic loss at late stages of the disease. |
format |
Article in Journal/Newspaper |
author |
Gomez‐Arboledas, Angela Fonseca, Maria I Kramar, Enikö Chu, Shu‐Hui Schartz, Nicole D Selvan, Purnika Wood, Marcelo A Tenner, Andrea J |
author_facet |
Gomez‐Arboledas, Angela Fonseca, Maria I Kramar, Enikö Chu, Shu‐Hui Schartz, Nicole D Selvan, Purnika Wood, Marcelo A Tenner, Andrea J |
author_sort |
Gomez‐Arboledas, Angela |
title |
C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
title_short |
C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
title_full |
C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
title_fullStr |
C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
title_full_unstemmed |
C5aR1 signaling promotes region‐ and age‐dependent synaptic pruning in models of Alzheimer's disease |
title_sort |
c5ar1 signaling promotes region‐ and age‐dependent synaptic pruning in models of alzheimer's disease |
publisher |
eScholarship, University of California |
publishDate |
2024 |
url |
https://escholarship.org/uc/item/68p1f01h |
op_coverage |
2173 - 2190 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Alzheimer's & Dementia, vol 20, iss 3 |
op_relation |
qt68p1f01h https://escholarship.org/uc/item/68p1f01h |
op_rights |
public |
_version_ |
1798842196982497280 |