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Abstract: PO1225

The Plasma Factor Beta-2 Microglobulin Drives Cognitive Impairment in ESRD

Session Information

Category: Dialysis

  • 701 Dialysis: Hemodialysis and Frequent Dialysis

Authors

  • Czirr, Eva, Alkahest Inc, San Carlos, California, United States
  • Le, David, Alkahest Inc, San Carlos, California, United States
  • Yang, Cindy F., Alkahest Inc, San Carlos, California, United States
  • Chand, Shreya, Alkahest Inc, San Carlos, California, United States
  • Gulati, Jyotasana, Alkahest Inc, San Carlos, California, United States
  • Lohr, Scott C., Alkahest Inc, San Carlos, California, United States
  • Minami, Sakura, Alkahest Inc, San Carlos, California, United States
Background

Our goal is to decode changes in the plasma proteome in age and disease to identify novel therapeutic targets. We and others have shown that administration of aged human plasma in young immunodeficient mice results in impaired neurogenesis and cognition. We are now extending these findings to plasma from end-stage renal disease (ESRD) subjects undergoing hemodialysis (HD). The prevalence of chronic kidney disease increases with age, and hemodialysis patients have a high incidence of cognitive impairment. The causes for this cognitive impairment are not fully understood and we hypothesize that plasma proteins, specifically beta-2 microglobulin (b2M) are a contributing factor. B2M has been identified as a detrimental pro-aging factor in mice, however aging increases b2M levels moderately by about 1.5 – 2-fold, while they are elevated up to 80-fold in ESRD-HD.

Methods

Plasma was collected from healthy controls and matched ESRD-HD subjects. HD plasma was depleted of b2M by AKST1210, a b2M removal device. Proteomic analysis was performed using affinity-based and mass spectrometry platforms. Plasma was administered IV into young immunodeficient NSG (NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ) mice, followed by behavioral testing, and histological and molecular analysis. B2M was administered IP to wild-type (WT; C57BL/6) mice, followed by similar analyses.

Results

Injection of ESRD-HD plasma into young NSG mice resulted in cognitive impairment and molecular changes in the brain. Proteomic analysis of the plasma revealed many changes, with b2M as one of the most elevated proteins. We found that peripheral b2M injections lead to concentration dependent changes in cognition, neurogenesis, and synapse density. When we depleted plasma from ESRD-HD subjects using AKST1210 b2M levels were highly reduced and the proteomic profile was shifted towards healthy control plasma. Injection of depleted plasma into young NSG mice rescued some of the detrimental changes caused by undepleted plasma suggesting that removal of b2M has beneficial effects.

Conclusion

Taken together, our data shows that plasma-derived factors can impact cognition and suggests that accumulation of detrimental factors such as b2M contributes to the high incidence of cognitive deficits in ESRD-HD subjects.

Funding

  • Commercial Support