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Liver-expressed antimicrobial peptide 2 elevation contributes to age-associated cognitive decline
Jing Tian, … , Jeffrey M. Zigman, Heng Du
Jing Tian, … , Jeffrey M. Zigman, Heng Du
Published May 22, 2023
Citation Information: JCI Insight. 2023;8(10):e166175. https://doi.org/10.1172/jci.insight.166175.
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Research Article Aging Neuroscience

Liver-expressed antimicrobial peptide 2 elevation contributes to age-associated cognitive decline

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Abstract

Elderly individuals frequently report cognitive decline, while various studies indicate hippocampal functional declines with advancing age. Hippocampal function is influenced by ghrelin through hippocampus-expressed growth hormone secretagogue receptor (GHSR). Liver-expressed antimicrobial peptide 2 (LEAP2) is an endogenous GHSR antagonist that attenuates ghrelin signaling. Here, we measured plasma ghrelin and LEAP2 levels in a cohort of cognitively normal individuals older than 60 and found that LEAP2 increased with age while ghrelin (also referred to in literature as “acyl-ghrelin”) marginally declined. In this cohort, plasma LEAP2/ghrelin molar ratios were inversely associated with Mini-Mental State Examination scores. Studies in mice showed an age-dependent inverse relationship between plasma LEAP2/ghrelin molar ratio and hippocampal lesions. In aged mice, restoration of the LEAP2/ghrelin balance to youth-associated levels with lentiviral shRNA Leap2 downregulation improved cognitive performance and mitigated various age-related hippocampal deficiencies such as CA1 region synaptic loss, declines in neurogenesis, and neuroinflammation. Our data collectively suggest that LEAP2/ghrelin molar ratio elevation may adversely affect hippocampal function and, consequently, cognitive performance; thus, it may serve as a biomarker of age-related cognitive decline. Moreover, targeting LEAP2 and ghrelin in a manner that lowers the plasma LEAP2/ghrelin molar ratio could benefit cognitive performance in elderly individuals for rejuvenation of memory.

Authors

Jing Tian, Lan Guo, Tienju Wang, Kun Jia, Russell H. Swerdlow, Jeffrey M. Zigman, Heng Du

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Figure 1

Age-associated change of plasma LEAP2, ghrelin, and LEAP2/ghrelin ratio in the elderly.

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Age-associated change of plasma LEAP2, ghrelin, and LEAP2/ghrelin ratio ...
(A–E) Correlation between age and plasma ghrelin (A), plasma total ghrelin (B), plasma LEAP2 (C), plasma LEAP2/ghrelin molar ratio (D), and BMI (E) were calculated using 2-tailed Pearson correlation coefficients. n = 19. (F–H) Correlation between BMI and plasma LEAP2 (F), plasma ghrelin (G), and plasma LEAP2/ghrelin molar ratio (H) were calculated using 2-tailed Pearson correlation coefficients. n = 19. (I–K) Correlation between plasma growth hormone and plasma LEAP2 (I), plasma ghrelin (J), and plasma total ghrelin (K) were calculated using 2-tailed Pearson correlation coefficients. n = 19.

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

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