Cited by 16Regulation of Appetite and ObesityDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Tian, Jing, Guo, Lan, Wang, Tienju, Jia, Kun, Swerdlow, Russell H., Zigman, Jeffrey M., Du, Heng·2023·JCI Insight

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.

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Crossref · 10.1172/jci.insight.166175

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  • Central ghrelin signaling plays a pivotal role in regulating food intake, hippocampal synaptic plasticity and neurogenesis, anxiety, depression, and cognitive function.

    “The central ghrelin signaling plays a pivotal role in diverse physiological functions, including the regulation of food intake, hippocampal synaptic plasticity and neurogenesis, anxiety, depression, and cognitive function.”
  • Age-related reductions in ghrelin signaling are associated with a decline in cognitive function.

    “age-related reductions in ghrelin signaling have been associated with a decline in cognitive function.”
  • In the elderly, an age-dependent reduction in plasma ghrelin and an elevated ratio of plasma LEAP2/ghrelin are associated with cognitive impairment.

    “A recent study in the elderly reported an age-dependent reduction in plasma ghrelin and an elevated ratio of plasma liver-expressed antimicrobial peptide 2 (LEAP2)/ghrelin, which is associated with cognitive impairment.”
  • Reducing the plasma LEAP2/ghrelin ratio reversed cognitive deficits in aged mice by restoring hippocampal neurogenesis, alleviating synaptic loss, and inhibiting neuroinflammation.

    “reducing the plasma LEAP2/ghrelin ratio reversed cognitive deficits in aged mice by restoring hippocampal neurogenesis, alleviating synaptic loss, and inhibiting neuroinflammation.”

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Authors
Tian, J., Guo, L., Wang, T., Jia, K., Swerdlow, R. H., Zigman, J. M., & Du, H.
Affiliations
  • Department of Pharmacology and Toxicology and
  • University of Kansas (US)
  • University of Kansas Medical Center (US)
  • The University of Texas Southwestern Medical Center (US)
Corresponding author
Du, Heng
Venue
JCI Insight
Published
2023-05-22
Volume
8
Issue
10
ISSN
2379-3708 (ISSN-L)
OpenAlex
W4377164066
Cited by
16
References
96
Citations by year
2026: 1 · 2025: 7 · 2024: 6 · 2023: 2
FWCI
2.38
Type
journal article
Language
en
Open access
Locations
  • JCI Insight (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • KU ScholarWorks (The University of Kansas) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01AG053588,R01AG059753,R01AG075108, P30 AG035982, P30 AG072973)
  • BrightFocus Foundation (A20201159S, A2022036S)
  • Higuchi Biosciences Center research grant (N/A)
  • KU career development grant (2302009)
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
LEAP2, ghrelin, age-related cognitive decline, hippocampal function, growth hormone secretagogue receptor, Mini-Mental State Examination, neurogenesis, neuroinflammation, biomarkers, aged mice
MeSH terms
Aging, Animals, Blood Proteins, Hippocampus, Humans, Middle Aged, Antimicrobial Cationic Peptides, Mice, Ghrelin, Receptors, Ghrelin, Cognitive Dysfunction, Hepcidins

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