Plasma dilution improves cognition and attenuates neuroinflammation in old mice
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ORIGINAL ARTICLE
Plasma dilution improves cognition and attenuates neuroinflammation in old mice Melod Mehdipour & Taha Mehdipour & Colin M. Skinner & Nathan Wong & Chao Liu & Chia-Chien Chen & Ok Hee Jeon & Yi Zuo & Michael J. Conboy & Irina M. Conboy
Received: 7 August 2020 / Accepted: 1 November 2020 # The Author(s) 2020
Abstract Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescenceassociated secretory phenotype (SASP) as the main M. Mehdipour : T. Mehdipour : C. M. Skinner : N. Wong : C. Liu : M. J. Conboy : I. M. Conboy (*) Department of Bioengineering and QB3, UC Berkeley, Berkeley, CA, USA e-mail: [email protected] C. 2-fold change with p < 0.05, we focused on the comparative levels of the proteins that directly regulate brain health, including receptors that are present on neurons, microglia, or other brain resident cells; ligands that influence proliferation and/or differentiation of neural cells; and signaling proteins that affect neuroplasticity or are neuroprotective. These studies identified 15 proteins that are directly significant for brain health, maintenance, and repair and that are changed in the TPE proteome, and 11 such proteins changed in the mouse NBE proteome. Interestingly in both species, dilution of old plasma ultimately resulted in a lasting elevation (not decline) of these determinants, which is consistent with our general conclusion on a resetting of the molecular signaling milieu to health (Fig. 5). Interestingly, proteins that influence multiple parameters of brain health were simultaneously modulated by the NBE and TPE, therefore providing a mechanism for improving multiple brain health aspects at once: enhancing brain function and synaptic plasticity, improving neuroprotection, attenuating neuroinflammation, diminishing neurotoxicity, and enhancing proliferation and differentiation of neural stem cells (Table 1). These results confirm and extrapolate the positive effects of old plasma dilution on the brain by demonstrating a lasting recalibration of systemically present molecular determinants that have direct effects on brain health and function.
Evolutionarily conserved effects of NBE and TPE on systemic proteins with direct influence on the brain
Plasma exchange is currently FDA approved for other diseases, a
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