이리신은 그리스 신화에 나오는 '전령의 여신' 이리스(iris)를 따서 작명한 호르몬. 근육 조직에서 만들어져서 혈액을 통해 온몸에 전달되는 신호전달 단백질
'네이처'지에서 이리신이 지방의 저장소인 백색지방이 갈색지방처럼 작동하게 해서, 운동 효율을 높이며, 운동을 통해 분비를 왕성하게 할 수 있다고 밝혀 화제
하버드 의대 연구진은 운동을 하면, 근육세포에서 많이 만들어지는 FNDC5 단백질이 112개 길이의 아미노산 조각으로 잘려 혈관을 타고, 백색지방을 갈색지방처럼 활동하게 만든다는 것을 확인
이리신에 대해 놀라운 점. 사람과 생쥐에서 아미노산 112개의 서열이 100% 같다. 인슐린의 경우 85%인 것을 보면, 진화론적으로 굉장히 중요한 호르몬
치매에 걸리게 만든 쥐를 1시간동안 수영을 시켰더니 인지기능이 개선되었는데, 이리신 전달 경로를 차단하자 인지기능은 이전처럼 저하. 치매 모델 쥐에서 이리신 수치를 높였더니, 신경세포 신호전달 부위의 시냅스가 회복
이리신은 뼈에도 영향을 미치는 것으로 밝혀졌다. 꾸준하게 운동을 하면 이리신이 분비되어 골형성세포를 자극해서 골량을 증가시킨다.
'이리신'이라는 호르몬은 운동을 통해 분비되며, 운동 효율을 높여 다이어트를 도와주고, 학습 인지기능을 향상시키며, 치매 증상을 완화하고, 골다공증을 예방 및 개선
이리신, 알츠하이머, 치매 예방, hormone irisin in amyloid beta reduction
운동하는 동안 분비되는 호르몬인 '이리신'이 알츠하이머병을 예방하는 데 효과가 있는 것으로 나타났다. 알츠하이머병은 치매를 일으키는 가장 흔한 퇴행성 뇌질환이다.
미국 매사추세츠종합병원 유전 및 노화 연구실에 따르면 운동할 때 만들어지는 호르몬인 이리신이 알츠하이머병의 특징인 플라크와 단백질 타우 엉킴을 모두 감소시키는 것으로 밝혀졌다. 이에 따라 연구팀은 이 호르몬을 기반으로 한 치료법이 알츠하이머병 치료의 새 지평을 열어줄 것으로 기대했다.
연구팀은 이전에 개발한 알츠하이머병의 첫 번째 3차원 인간 세포 배양 모델을 기반으로 뇌의 아밀로이드 베타에 대한 이리신의 영향을 분석했다. 아밀로이드 베타는 알츠하이머 환자의 뇌에서 발견되는 아밀로이드 플라크의 주성분이다.
이전의 쥐 실험에서 운동은 아밀로이드 베타가 쌓이는 것을 감소시키는 것으로 나타났지만 그 방법은 명확하게 밝혀지지 않았었다.
이번 연구에서 운동할 때 근육에서 유래하는 호르몬인 이리신 수준의 증가는 지방 조직의 포도당과 지질 대사를 조절하며, 백색 지방 조직의 갈색 화를 촉진해 에너지 소비를 증가시키는 것으로 나타났다. 알츠하이머 환자는 이리신 수치가 낮다.
연구팀의 최세훈 박사는 병원 보도 자료를 통해 "첫째 이리신을 이용한 치료가 아밀로이드 베타 병리의 현저한 감소를 가져 왔다는 것을 발견했고, 둘째로는 이리신의 이러한 효과가 뇌의 성상 세포(별 세포)에서 분비되는 네프릴리신 활성 증가에 기인한다는 사실을 알아냈다"고 밝혔다.
네프릴리신은 아밀로이드 베타를 분해하는 효소. 알츠하이머병에 걸린 쥐를 운동이나 다른 조건에 노출시켰을 때 쥐의 뇌에서 네프릴리신이 증가하면서 아밀로이드 베타가 감소하는 것으로 나타났다.
연구팀은 "이리신은 쥐와 인간의 뇌 모두에 존재하므로 연구에 유용한 표적이 된다"며 "세포가 네프릴리신 수치를 증가시키는 과정을 확인함으로써 이를 더욱 발전시킬 수 있게 됐다"고 설명했다.
연구팀의 루돌프 탄지 박사는 "실험쥐의 혈류에 주입된 이리신은 뇌로 들어가 잠재적으로 치료제로서 유용할 수 있었다"며 "이번 연구 결과에 따르면 운동할 때 나오는 이리신은 네프릴리신 수치를 증가시킴으로써 아밀로이드 베타 부담을 줄이는 주요 매개체로 밝혀졌고 이는 알츠하이머병의 예방과 치료에 새로운 경로를 제시한다"고 말했다.
이번 연구 결과(Irisin reduces amyloid-b by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling)는 학술지 '뉴런(Neuron)'에 실렸다.
The role of exercise-induced hormone irisin in amyloid beta reduction
In a recent study published in Neuron, researchers explored the biological mechanisms by which exercise-induced irisin attenuates amyloid-beta (Aβ) pathology in Alzheimer’s disease (AD).
Background
AD, a form of dementia, is characterized by progressive memory loss and severe cognitive impairment. Aβ protein deposition is a pathological hallmark of AD. Physical exercise has been shown to reduce Aβ deposition and neuroinflammation in AD mouse models. Irisin, an exercise-induced hormone, regulates lipid and glucose metabolism in adipose tissues and increases energy expenditure. Lower irisin levels have been reported in AD patients and AD murine models.
About the study
In the present study, researchers elucidated mechanisms underlying irisin-induced Aβ reduction in AD.
A three-dimensional (3D) human brain cell culture model of AD with robust Aβ generation was used, followed by a tau pathology (3D-AD) model. Irisin was administered to differentiated ReN cells that expressed familial AD-related APPSwedish/London amino acid substitutions (ReN-GA) or presenilin-1 and APPSwedish/London amino acid substitutions (ReN-mGAP) for two weeks at concentrations of 5.0 as well as 500 nanograms per mL. From two- or five-week differentiated three-dimensional cultures, samples of conditioned medium and cell pellets (3D gel) were obtained for analysis.
The enzyme lactate dehydrogenase was employed to detect cell death or cytotoxicity. Brain-derived neurotrophic factor (BDNF) expression was measured. Western blotting was done using 6E10 or G12A antibodies. Calcium stimulation and quick time-lapse imaging were used to measure the spontaneous activity of active cells in three-dimensional cultures after five weeks of differentiation.
The researchers investigated whether irisin may lower Aβ levels by increasing Aβ phagocytosis or enzymatic breakdown. In conditioned media comprising irisin-treated three-dimensional-AD cells, the researchers examined the levels of secreted neprilysin (secNEP) and insulin-degrading enzyme (secIDE), which are proteases released by astrocytes that can reduce Aβ levels.
The action of sacubitril, a neprilysin inhibitor, was examined in conditioned media comprising three-dimensional cultures. Human-induced pluripotent stem-cell-derived astrocyte (hiPSC-Astro) cells were treated with irisin to see if they were the source of the irisin-induced rise in secreted NEP.
Integrin αV and β5 subunit expression in ReN-mGAP and ReN-GA cells were validated using mass spectrometry (MS) and western blot analyses, respectively. Integrin β5 (ITGB5) activity was reduced genetically in ReN-GA and pharmacologically in ReN-mGAP cells to investigate whether integrin αV/β5 receptors were necessary for irisin to lower Aβ levels.
In five-week irisin-treated ReN-GA cells, the researchers examined signal transducer and activator of transcription 3 (STAT3) gene expression using specific astrocyte reactivity markers such as Cp, C3, glial fibrillary acidic protein (GFAP), cluster of differentiation 44 (CD44), adhesion molecule with Ig-like domain 2 (Amigo2), epithelial membrane protein 1 (Emp1), and serpin family G member 1 (Serping1).
In irisin-treated cells, the levels of astrocyte reactivity markers, S100 calcium-binding protein B (S100b), and GFAP were measured. Single-cell ribonucleic acid sequencing (scRNA-seq) was performed to examine irisin-induced cell-specific transcriptome alterations,
Results
The exercise-induced myokine, irisin, increased neprilysin production, which reduced A pathology in the AD culture. Integrin αV/β5 was the irisin receptor on astrocytes necessary to promote neprilysin secretion, which was achieved by downregulating the extracellular-signal-regulated kinase (ERK)-STAT3 signaling. At 500 nanograms per mL concentrations, irisin dramatically lowered Aβ-40 and 42 expressions in five-week ReN-GA cells and cellular pellets.
After five weeks of cellular differentiation, 500 nanograms per mL of irisin decreased Aβ-40 and 42 expressions in conditioned media and only Aβ42 expression in ReN-mGAP pellets, indicating more severe AD pathology than ReN-GA.
In five-week three-dimensional-AD cultures, irisin treatment did not enhance LDH release, showing that the irisin-induced Aβ reduction did not occur from cell death. Instead, it lowered LDH secretion at 500 nanograms per mL in five-week three-dimensional-AD cells at the time of endogenous loss of cells, showing neuroprotective benefits. Irisin showed no effect on BDNF expression in the five-week three-dimensional-AD cultures, demonstrating that the drop in Aβ caused by irisin was not BDNF-regulated.
Irisin quickly activated integrin receptors, as evidenced by increased phosphorylated focal adhesion kinase (p-FAK) and cyclic AMP response element-binding protein (CREB) phosphorylation in ReN-mGAP and hiPSC-Astro cultures. Irisin increased integrin signaling in the AD- and hiPSC-Astro cultures, based on the findings. Irisin lowered the expressions of nuclear factor kappa B (NF-kB) p65, complement C3 (C3), C3a receptor (C3aR), and apolipoprotein E (APOE) in the gels of five-week ReN-GA cells. Irisin treatment did not affect amyloid precursor protein (APP) processing.
In the AD cultures, irisin decreased the quantity and size of dystrophic neurites as well as cell hyperexcitability and boosted secNEP levels. Sacubitril inhibited secNEP activity in the three-dimensional culture medium.
Irisin and sacubitril co-treatment dramatically increased Aβ42 expression in AD cultures, indicating that irisin required increased secNEP activity to decrease Aβ42 expression. L-a-aminoadipate (L-AAA) therapy significantly reduced S100b and ITGB5 expression among ReN-mGAP cells, indicating that ITGB5 was mainly expressed in astrocytes in the 3D-AD model.
The capacity of irisin to lower STAT3, C3aR, and NF-kB p65 was abolished when combined with an integrin αV/β5 antibody. Irisin inhibited the expression of reactive astrocyte genes and proteins. Irisin decreased STAT3 levels by blocking interleukin-6 (IL-6)/ERK signaling, enhancing secNEP release. A1 inducer treatment decreased neprilysin expression in hiPSC-Astro cell lysates. Irisin also lowered the amount of phosphorylated tau protein in the body.
Conclusion
Overall, the study findings showed that irisin significantly reduced Aβ pathology by boosting the astrocytic release of the Aβ-degrading enzyme neprilysin, mediated via ERK-STAT3 signaling downregulation. The findings lend support to the development of irisin as a possible therapeutic target for Alzheimer's disease.
Journal reference:
Kim et al., Irisin reduces amyloid-β by inducing the release of neprilysin from astrocytes following downregulation of ERK-STAT3 signaling, Neuron (2023)