CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury

Mary T. Joy, Einor Ben Assayag, Dalia Shabashov-Stone, Sigal Liraz-Zaltsman, Jose Mazzitelli, Marcela Arenas, Nora Abduljawad, Efrat Kliper, Amos D. Korczyn, Nikita S. Thareja, Efrat L. Kesner, Miou Zhou, Shan Huang, Tawnie K. Silva, Noomi Katz, Natan M. Bornstein, Alcino J. Silva, Esther Shohami, S. Thomas Carmichael*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.

Original languageEnglish
Pages (from-to)1143-1157.e13
JournalCell
Volume176
Issue number5
DOIs
StatePublished - 21 Feb 2019

Funding

FundersFunder number
American Heart Foundation16POST27710039
Alzheimer's Association16-442861
American Federation for Aging ResearchRAG11482
American Hungarian Foundation
Stanford University
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
University of California, Los Angeles
United States-Israel Binational Science Foundation2011344

    Keywords

    • MOCA
    • NIHSS
    • astrocyte
    • axon
    • axonal sprouting
    • dendritic spine
    • microglia
    • motor
    • premotor

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