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.

Amyloid beta protein (A[beta]) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of A[beta] and its physiological role in non-disease states is not clear. In these studies, low doses of A[beta] enhanced memory retention in two memory tasks and enhanced acetylcholine production in the hippocampus in vivo. We then tested whether endogenous A[beta] has a role in learning and memory in young, cognitively intact mice by blocking endogenous A[beta] in healthy 2-month-old CD-1 mice. Blocking A[beta] with antibody to A[beta] or DFFVG (which blocks A[beta] binding) or decreasing A[beta] expression with an antisense directed at the A[beta] precursor APP all resulted in impaired learning in T-maze foot-shock avoidance. Finally, A[beta]1-42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to A[beta] inhibited hippocampal LTP. These results indicate that in normal healthy young animals the presence of A[beta] is important for learning and memory.

Amyloid-β protein (Aβ) is well recognized as having a significant role in the pathogenesis of Alzheimer's disease (AD). The reason for the presence of Aβ and its physiological role in non-disease states is not clear. In these studies, low doses of Aβ enhanced memory retention in two memory tasks and enhanced acetylecholine production in the hippocampus in vivo. We then tested whether endogenous Aβ has a role in learning and memory in young, cognitively intact mice by blocking endogenous Aβ in healthy 2-month-old CD-1 mice. Blocking Aβ with antibody to Aβ or DFFVG (which blocks Aβ binding) or decreasing Aβ expression with antisense directed at the Aβ precursor, AβPP, all resulted in impaired learning in T-maze foot-shock avoidance. Finally, Aβ1−42 facilitated induction and maintenance of long term potentiation in hippocampal slices, whereas antibodies to Aβ inhibited hippocampal LTP. In conclusion, these results indicate that in normal healthy young animals the presence of Aβ is important for learning and memory.