Chemerin-9 Peptide Enhances Memory and Ameliorates Aβ_1–42-Induced Object Memory Impairment in Mice

Abstract

Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid β 1-42 (Aβ 1-42) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aβ 1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aβ 1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aβ 1-42. Meanwhile, C9 also significantly inhibited Aβ 1-42-induced increases in the levels of pro-inflammatory cytokines such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aβ 1-42-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.

Bidirectional communication between brain and visceral white adipose tissue: Its potential impact on Alzheimer's disease

“…For example, vWAT contains plenty of adipocytes that are capable to secrete multiple hormones. Many of these hormones have been proved to participate in the pathogenesis of AD ( Table 1 ), including metabolism of Aβ, 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 phosphorylation of tau, 182 , 183 , 189 , 191 , 192 hippocampal neurogenesis, 181 , 193 , 194 neurodegeneration, 181 , 195 synaptic function, 196 , 197 , 198 , 199 , 200 neuroinflammation 186 , 201 , 202 , 203 , 204 , 205 , 206 and oxidative stress. 181 , 182 , 184 , 206 , 207 , 208 All the findings indicate the vWAT-derived hormones could be a mediator between vWAT and AD.…”

Chemerin-9 Attenuates Experimental Abdominal Aortic Aneurysm Formation in ApoE−/− Mice

“…Chemerin-9, an analog of chemerin, has a higher affinity for CMKLR1 and functions as an anti-inflammatory regulator to inhibit the development of atherosclerosis, Alzheimer's disease, and pancreatogenic diabetes [22][23][24]. However, the role of chemerin-9 in the biological behavior of AAA has so far been reported.…”

“…Chemerin-9 (149-157), comprising nine amino acids from the C-terminus of chemerin, retains most agonist activity [22]. In vivo, chemerin-9 exerts an anti-inflammatory effect by targeting CMKLR1, thus restraining the development of several diseases, including atherosclerosis, Alzheimer's disease, and pancreatogenic diabetes [22][23][24]. However, the role of chemerin-9 in AAA behavior has not yet been reported.…”

The Chemerin-CMKLR1 Axis is Functionally important for Central Regulation of Energy Homeostasis

“…In support, central administration of the nonapeptide chemerin-9, derived from the C-terminus of the chemerin precursor, enhances cognition and memory performance. Additionally, chemerin-9 protects against neuroinflammation caused by amyloid-β and memory impairment caused by Aβ42 ( Lei et al, 2020 ). Furthermore, in a mouse model of Alzheimer’s CMKLR1 deficiency improves cognitive deficits ( Zhang et al, 2020 ).…”

“…Given that high-fat feeding increases circulating levels of chemerin, induces inflammatory markers and results in a decline of cognitive performance ( Helfer and Wu 2018 ; Tan and Norhaizan 2019 ; Léniz et al, 2022 ) and recent studies have implicated the chemerin-CMKLR1 axis in cognitive function ( Lei et al, 2020 ; Zhang et al, 2020 ), in this study we aimed to test the link between the hypothalamic chemerin-CMKLR1 pathway, neuroinflammation and cognition after high-fat feeding. We used a combination of pharmacological and genetic manipulation approaches to block CMKLR1 signaling in the hypothalamus and showed that modulating chemerin function has a profound effect on body weight of high-fat fed rats acutely and chronically.…”