Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington's disease

Abstract

Background: Huntington's disease (HD) starts its pathology long before clinical manifestation, however, there is no therapy to cure it completely and only a few studies have been reported for delaying the progression of HD. Recently, it has been shown that heterochronic parabiosis can modulate the neurodegenerative diseases. Despite the importance of the transportation process of positive factors during heterochronic parabiosis, there were limited understandings because the transportation process is nanoscale, which makes it difficult to identify the messenger unit. We demonstrated that heterochronic parabiosis could modulate HD in R6/2 mice model, and identified the messenger unit for transferring positive factors in the young blood serum.

Methods: R6/2 mice were surgically connected with young wild-type mice (n = 13), old wild-type mice (n = 8), or R6/2 mice (n = 6) to examine the effect of heterochronic parabiosis. Parabionts composed of 5- to 6-week-old transgenic and wild-type mice were observed for 6 weeks in a single cage. The in vitro cellular model of HD cells were treated by the blood serum of the young or old mice, and by the exosomes isolated from thereof. The in vitro cellular model of HD were developed by differentiating neural stem cells cultured from SVZ of the brain.

Results: After the heterochronic parabiosis, the weight loss and survival of HD mice was improved. Also, mutant Huntingtin aggregation (EM48 p < 0.005), improvement of mitochondria dysfunction (PGC-1a p < 0.05, p-CREB/CREB p < 0.005), cell death (p53 p < 0.05, Bax p < 0.05, Cleaved-caspase3 p < 0.05), and cognition (DCX p < 0.5) showed a near complete restoration. In addition, treating in vitro cellular model of HD by the exosomes from young blood serum improved mutant Huntingtin aggregation (EM48 p < 0.05), mitochondria biogenesis (p-CREB/CREB p < 0.005), cell death (p53 p < 0.05, Bax p < 0.005, Cleaved-caspase3 p < 0.05, Bcl-2 p < 0.05), and cell proliferation (WST-1 p < 0.005).

Conclusions: We found that the overall pathology of HD could be improved by the shared blood circulation through heterochronic parabiosis, furthermore, we demonstrated that the exosomes could be messengers for transferring positive factors, showing the potential of exosomes from young blood for the amelioration of HD.