The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum–microglia crosstalk preventing disease progression in a mouse model of Huntington’s disease
Alba Di Pardo, Elena Ciaglia, Monica Cattaneo, Anna Maciąg, Francesco Montella, Valentina Lopardo, Anna Ferrario, Francesco Villa, Michele Madonna, Enrico Amico, Albino Carrizzo, Antonio Damato, Giuseppe Pepe, Federico Marracino, Alberto Auricchio, Carmine Vecchione, Vittorio Maglione, Annibale Alessandro Puca
Abstract
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 Q 111/111 ) expressed and secreted lower levels of BPIFB4, when compared with Htt expressing cells (STHdh Q 7/7 ), which correlated with a defective stress response to proteasome inhibition. Overexpression of LAV-BPIFB4 in STHdh Q 111/111 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 Q 111/111 dying cells were ineffective to induce a CD163 + IL-10 high pro-resolving microglia compared to normal STHdh Q 7/7 , 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.