Abstract

The neural functions of adropin, a secreted peptide highly expressed in the brain, have not been investigated. In humans, adropin is highly expressed in astrocytes and peaks during critical postnatal periods of brain development. Gene enrichment analysis of transcripts correlating with adropin expression suggests processes relevant to aging-related neurodegenerative diseases that vary with age and dementia state, possibly indicating survivor bias. In people aged <40 y and ‘old-old’ (>75 y) diagnosed with dementia, adropin correlates positively with genes involved in mitochondrial processes. In the ‘old-old’ without dementia adropin expression correlates positively with morphogenesis and synapse function. Potent neurotrophic responses in primary cultured neurons are consistent with adropin supporting the development and function of neural networks. Adropin expression in the ‘old-old’ also correlates positively with protein markers of tau-related neuropathologies and inflammation, particularly in those without dementia. How variation in brain adropin expression affects neurological aging was investigated using old (18-month) C57BL/6J mice. In mice adropin is expressed in neurons, oligodendrocyte progenitor cells, oligodendrocytes, and microglia and shows correlative relationships with groups of genes involved in neurodegeneration and cellular metabolism. Increasing adropin expression using transgenesis improved spatial learning and memory, novel object recognition, resilience to exposure to new environments, and reduced mRNA markers of inflammation in old mice. Treatment with synthetic adropin peptide also reversed age-related declines in cognitive functions and affected expression of genes involved in morphogenesis and cellular metabolism. Collectively, these results establish a link between adropin expression and neural energy metabolism and indicate a potential therapy against neurological aging.

Highlights

  • Aging associates with declining cognitive performance and capacity for tracking the “what/where/when” in our daily activities[1,2,3]

  • Energy Homeostasis Associated (ENHO) is highly expressed in all brain structures relative to other tissues (Fig. 1A) and is moderately (10%) higher in some areas of the male brain when compared to females (Fig. S1, S2A)

  • C Results from gene enrichment analysis showing biological processes responding to adropin[34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76] treatment. These results indicate that adropin functions support brain health during aging

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Summary

Introduction

Aging associates with declining cognitive performance and capacity for tracking the “what/where/when” in our daily activities (episodic memory)[1,2,3]. Modelling in silico suggests a signal sequence (adropin1-33) targets the secretory pathway[14,15,16]. The predicted secreted domain (adropin34-76) is sufficient for biological activity in cultured cells and rodent models[14,17,18,19,20,21,22,23,24,25,26]. The exact sequence and any posttranslational modifications of the mature peptide are not known

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