Liver-expressed antimicrobial peptide 2 elevation contributes to age-associated cognitive decline
Jing Tian, Lan Guo, Tienju Wang, Kun Jia, Russell H. Swerdlow, Jeffrey M. Zigman, Heng Du
Jing Tian, Lan Guo, Tienju Wang, Kun Jia, Russell H. Swerdlow, Jeffrey M. Zigman, Heng Du
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Research Article Aging Neuroscience

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

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 4

Hippocampal ghrelin signaling deregulation and pathology in old mice.

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Hippocampal ghrelin signaling deregulation and pathology in old mice. (A...
(A) Thirty-month-old (30M) mice showed increased plasma LEAP2 compared with 8M mice. (B and C) Plasma ghrelin (B) or total ghrelin (C) showed no change. (D) Plasma LEAP2/ghrelin molar ratio increased in 30M mice. (A–D) n = 9 mice per group. (E and F) Hippocampal GHSR/DRD1 heterodimerization by Duolink PLA assay. 8M, n = 5; 30M, n = 4; GHSR-null, n = 2. (F) Representative images. Scale bar: 20 μm (inset, scale bar: 5 μm). GHSR-null mice were used to verify Duolink PLA assay. (G and H) Hippocampal membrane–bound GHSR expression by membrane blot. β-III Tubulin was used as the loading control. 8M, n = 4; 30M, n = 4; GHSR-null, n = 2. (H) The representative images. GHSR-null mice were used to verify the specificity of membrane blot. The dots were run on the same membrane but were noncontiguous. (I and J) Synaptic density of hippocampal CA1 region was analyzed by colocalization of presynaptic marker (vGlut1) and postsynaptic marker (PSD95). 8M, n = 6; 30M, n = 6; GHSR-null, n = 4. (J) The 3D-reconstructed representative images. Scale bar: 100 μm (inset, scale bar: 20 μm). (K and L) The number of doublecortin+ (DCX+) neurons were counted in the dentate gyrus. 8M, n = 6; 30M, n = 6; GHSR-null, n = 4. (L) The 3D-reconstructed representative images. Adult neurogenesis was determined by DCX+ staining. Scale bar: 150 μm (inset, scale bar: 40 μm). GHSR-null, 8-month-old GHSR-null mice. Unpaired Student’s t test was used in A–E and G; 1-way ANOVA followed by Bonferroni post hoc analysis was used in I and K. *P < 0.05, **P < 0.01, ***P < 0.001. Sagittal brain slices that were 0.8–1 mm lateral to the medial plane were used in E and F, and slices 1–1.2 mm were used in I–L.