The longevity-associated variant of BPIFB4 improves a CXCR4-mediated striatum-microglia crosstalk preventing disease progression in a mouse model of Huntington's disease

被引：18

作者：

Di Pardo, Alba ^{[1
]}

Ciaglia, Elena ^{[2
]}

Cattaneo, Monica ^{[3
]}

Maciag, Anna ^{[3
]}

Montella, Francesco ^{[2
]}

Lopardo, Valentina ^{[2
]}

Ferrario, Anna ^{[3
]}

Villa, Francesco ^{[3
,6
]}

Madonna, Michele ^{[1
]}

Amico, Enrico ^{[1
]}

Carrizzo, Albino ^{[1
,2
]}

Damato, Antonio ^{[1
]}

Pepe, Giuseppe ^{[1
]}

Marracino, Federico ^{[1
]}

Auricchio, Alberto ^{[4
,5
]}

Vecchione, Carmine ^{[1
,2
]}

Maglione, Vittorio ^{[1
]}

Puca, Annibale A. ^{[2
,3
]}

机构：

[1] IRCCS Neuromed, I-86077 Pozzilli, Italy

[2] Univ Salerno, Dept Med Surg & Dent, Scuola Med Salernitana, I-84081 Baronissi, Italy

[3] IRCCS MultiMed, Cardiovasc Res Unit, I-20138 Milan, Italy

[4] TIGEM Telethon Inst Genet & Med, I-80078 Pozzuoli, Italy

[5] Univ Naples Federico II, Dept Translat Med, Naples, Italy

[6] Harvard Med Sch, Boston Childrens Hosp, Neurodev Behav Core, FM Kirby Neurobiol Ctr, Boston, MA 02115 USA

来源：

CELL DEATH & DISEASE | 2020年 / 11卷 / 07期

关键词：

CHEMOKINE CXCL12; GENE; PATHOGENESIS; ACTIVATION; CELLS; NEUROPATHOLOGY; PROGRAM;

D O I：

10.1038/s41419-020-02754-w

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：16

共 63 条

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