The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease: Cell Death and Disease

A. Di Pardo, E. Ciaglia, M. Cattaneo, A. Maciag, F. Montella, V. Lopardo, A. Ferrario, F. Villa, M. Madonna, E. Amico, A. Carrizzo, A. Damato, G. Pepe, F. Marracino, A. Auricchio, C. Vecchione, V. Maglione, A.A. Puca

Research output: Contribution to journalArticlepeer-review

Abstract

The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) has been found significantly enriched in long-living individuals. Neuroinflammation is a key player in Huntington’s disease (HD), a neurodegenerative disorder caused by neural death due to expanded CAG repeats encoding a long polyglutamine tract in the huntingtin protein (Htt). Herein, we showed that striatal-derived cell lines with expanded Htt (STHdh Q111/111) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q7/7), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q111/111 cells was able to rescue both the BPIFB4 secretory profile and the proliferative/survival response. According to a well-established immunomodulatory role of LAV-BPIFB4, conditioned media from LAV-BPIFB4-overexpressing STHdh Q111/111 cells were able to educate Immortalized Human Microglia—SV40 microglial cells. While STHdh Q111/111 dying cells were ineffective to induce a CD163 + IL-10high pro-resolving microglia compared to normal STHdh Q7/7, LAV-BPIFB4 transduction promptly restored the central immune control through a mechanism involving the stromal cell-derived factor-1. In line with the in vitro results, adeno-associated viral-mediated administration of LAV-BPIFB4 exerted a CXCR4-dependent neuroprotective action in vivo in the R6/2 HD mouse model by preventing important hallmarks of the disease including motor dysfunction, body weight loss, and mutant huntingtin protein aggregation. In this view, LAV-BPIFB4, due to its pleiotropic ability in both immune compartment and cellular homeostasis, may represent a candidate for developing new treatment for HD. © 2020, The Author(s).
Original languageEnglish
JournalCell Death Dis.
Volume11
Issue number7
DOIs
Publication statusPublished - 2020

Keywords

  • adeno associated virus vector
  • bactericidal permeability increasing fold containing family b member 4 protein
  • bactericidal permeability increasing protein
  • CD163 antigen
  • interleukin 10
  • messenger RNA
  • neuroprotective agent
  • plerixafor
  • proteasome inhibitor
  • stromal cell derived factor 1
  • unclassified drug
  • animal cell
  • animal experiment
  • animal model
  • animal tissue
  • Article
  • body weight loss
  • cell death
  • cell expansion
  • cell proliferation
  • cell surface
  • cell survival
  • controlled study
  • corpus striatum
  • disease exacerbation
  • female
  • gene overexpression
  • genetic variability
  • human
  • human cell
  • Huntington chorea
  • in vitro study
  • in vivo study
  • microglia
  • molecular interaction
  • motor dysfunction
  • mouse
  • neuroprotection
  • nonhuman
  • pleiotropy
  • priority journal
  • protein aggregation
  • protein secretion
  • STHdhQ111 cell line
  • target cell
  • wild type mouse

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