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Cited by 129Neuroinflammation and Neurodegeneration MechanismsAutophagy in Disease and TherapyAlzheimer's disease research and treatments

Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration

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Festa, Beatrice Paola, Siddiqi, Farah H., Jimenez-Sanchez, Maria, Won, Hyeran, Rob, Matea, Djajadikerta, Alvin, Stamatakou, Eleanna, Rubinsztein, David C.·2023·Neuron
DOI 10.1016/j.neuron.2023.04.006
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Abstract

In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.

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  • The progressive gait impairment and poor pole test performance of VavCre:hDNMT3A R822H BM recipients was reminiscent of a hypokinetic motor phenotype associated with parkinsonism that results from dopaminergic deficiencies.

    “The progressive gait impairment and poor performance in the pole test of the Vav Cre : hDNMT3A R822H BM recipients was reminiscent of a hypokinetic motor phenotype-associated with parkinsonism 58 that results from dopaminergic deficiencies.”

    From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [58]

    The Results describe motor deficits in Huntington’s disease mice and improvements after CCR5 depletion, but do not characterize those deficits as parkinsonian or link them to dopamine deficiency. A search of our copy for parkinsonism, the pole test, dopaminergic deficiency, and VavCre:hDNMT3A R822H recipients found no passage addressing the cited comparison. (LLM, conf=0.76)

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Cited by

Sorted by citations

Authors
Festa, B. P., Siddiqi, F. H., Jimenez-Sanchez, M., Won, H., Rob, M., Djajadikerta, A., Stamatakou, E., & Rubinsztein, D. C.
Affiliations
University of Cambridge (GB)
Corresponding author
Rubinsztein, David C.
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2023-07
Volume
111
Issue
13
Pages
2021-2037.e12
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/j.neuron.2023.04.006
OpenAlex
W4367056702
Cited by
129
References
8
Citations by year
2026: 36 · 2025: 45 · 2024: 32 · 2023: 16
FWCI
13.30
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Portal (King's College London) (publishedVersion, other-oa)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • Apollo
Funders
  • Wellcome Trust (095317/Z/11/Z)
  • European Union (860035)
  • H2020 Marie Skłodowska-Curie Actions
  • Alzheimer’s Research UK
  • Tau Consortium
  • Institut Pasteur
  • Medical Research Council
  • Horizon 2020
  • National Institutes of Health
  • UK Dementia Research Institute
  • Alzheimer's Society
  • NIHR Cambridge Biomedical Research Centre (BRC-1215-20014)
  • National Institute for Health and Care Research
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
neuron-microglia communication, CCR5, neuronal autophagy, mTORC1, neurodegeneration, Huntington's disease, tauopathy, protein aggregate clearance, microglial activation, CCR5 inhibition
MeSH terms
Mechanistic Target of Rapamycin Complex 1, Animals, Autophagy, Huntington Disease, Proteins, Signal Transduction, Microglia, Neurodegenerative Diseases, Mice

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