Adropin correlates with aging-related neuropathology in humans and improves cognitive function in aging mice

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.

Neurovascular protection by adropin in experimental ischemic stroke through an endothelial nitric oxide synthase-dependent mechanism

“…S1A and S1B ). Minimal adropin immunoreactivity was detected in GFAP or Iba1 immunoreactive cells (data not shown), in agreement with our recent finding that adropin is expressed in neuronal and endothelial cells using the adropin-internal ribosomal entry sequence (IRES)-Cre-tdTomato reporter mouse [ 14 ]. In addition to the cell types expressing adropin in the brain, we also investigated the expression of adropin in different organs of adult male C57BL/6J naïve mice.…”

“…We found that adropin treatment provides robust improvement of sensorimotor function in stroke mice. Importantly, we found that the protective effects of adropin are also observed in aged mice subjected to ischemic stroke and that adropin overexpressing mice show better recognition memory performance, which agrees with our recent observation that adropin treatment or adropin transgenic overexpression can significantly improve cognitive function in aged mice [ 14 ]. Taken together, our data suggest that maintenance of brain adropin level could be pivotal for mitigating ischemic brain damage and improve long-term functional outcomes.…”

“…Since knowledge of the cellular distribution of adropin in the brain is limited, we determined the cell types expressing this peptide in the naïve mouse brain. We used double immunostaining with a highly specific adropin monoclonal antibody or an adropin-internal ribosomal entry sequence (IRES)-Cre-TdTomato reporter mouse [ 14 ]. We consistently found that adropin is highly expressed in brain endothelial cells and neurons, with minimal expression in astrocytes or microglial cells.…”

“…There is also emerging evidence of low levels of serum adropin correlating with endothelial dysfunction and severity of coronary heart disease [ 11 , 12 ]. Adropin protein levels in the brain and plasma decrease with the aging of rats [ 13 ], mice [ 14 ], and humans [ 15 , 16 ]. A recent study found lower serum adropin levels in patients with acute ischemic stroke compared to controls [ 17 ].…”

Role of Adropin in Cardiometabolic Disorders: From Pathophysiological Mechanisms to Therapeutic Target

“…Adropin, a highly conserved 76 amino peptide hormone, secreted primarily by the liver, recently emerged as an important regulatory component of the vascular endothelium [3]. Apart from the well-established role of adropin in metabolic regulation, particularly with regard to glucose metabolism and insulin sensitivity in the heart, liver and skeletal muscle, accumulating data suggest that adropin has important implications on CV pathology [4][5][6]. In fact, stimulation of adropin-mediated pathways has been shown to improve endothelial function and reduce inflammation, thus ameliorating its detrimental effects.…”