Molecular interaction between type 2 diabetes and Alzheimer’s disease through cross-seeding of protein misfolding

转基因小鼠 蛋白质聚集 淀粉样蛋白(真菌学) 转基因 蛋白质折叠 纤维 小岛 胰淀素 细胞生物学 体内 生物 阿尔茨海默病 化学 疾病 生物化学 内分泌学 医学 内科学 病理 糖尿病 遗传学 基因
作者
Inés Moreno‐González,George A. Edwards,Natalia Salvadores,Mohammad Shahnawaz,Rodrigo Díaz‐Espinoza,Claudio Soto
出处
期刊:Molecular Psychiatry [Springer Nature]
卷期号:22 (9): 1327-1334 被引量:156
标识
DOI:10.1038/mp.2016.230
摘要

Numerous epidemiological studies have shown a significantly higher risk for development of Alzheimer’s disease (AD) in patients affected by type 2 diabetes (T2D), but the molecular mechanism responsible for this association is presently unknown. Both diseases are considered protein misfolding disorders associated with the accumulation of protein aggregates; amyloid-beta (Aβ) and tau in the brain during AD, and islet amyloid polypeptide (IAPP) in pancreatic islets in T2D. Formation and accumulation of these proteins follows a seeding-nucleation model, where a misfolded aggregate or ‘seed’ promotes the rapid misfolding and aggregation of the native protein. Our underlying hypothesis is that misfolded IAPP produced in T2D potentiates AD pathology by cross-seeding Aβ, providing a molecular explanation for the link between these diseases. Here, we examined how misfolded IAPP affects Aβ aggregation and AD pathology in vitro and in vivo. We observed that addition of IAPP seeds accelerates Aβ aggregation in vitro in a seeding-like manner and the resulting fibrils are composed of both peptides. Transgenic animals expressing both human proteins exhibited exacerbated AD-like pathology compared with AD transgenic mice or AD transgenic animals with type 1 diabetes (T1D). Remarkably, IAPP colocalized with amyloid plaques in brain parenchymal deposits, suggesting that these peptides may directly interact and aggravate the disease. Furthermore, inoculation of pancreatic IAPP aggregates into the brains of AD transgenic mice resulted in more severe AD pathology and significantly greater memory impairments than untreated animals. These data provide a proof-of-concept for a new disease mechanism involving the interaction of misfolded proteins through cross-seeding events which may contribute to accelerate or exacerbate disease pathogenesis. Our findings could shed light on understanding the linkage between T2D and AD, two of the most prevalent protein misfolding disorders.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
易川发布了新的文献求助10
1秒前
1秒前
2秒前
ronnie完成签到,获得积分10
2秒前
2秒前
碧蓝丹烟完成签到 ,获得积分10
3秒前
3秒前
3秒前
爱听歌的从筠完成签到,获得积分20
4秒前
spenley完成签到,获得积分10
4秒前
小二郎应助niekyang采纳,获得10
4秒前
ding应助AlwaysKim采纳,获得10
6秒前
杨冰完成签到,获得积分10
6秒前
Metx完成签到 ,获得积分10
6秒前
善学以致用应助Hiker采纳,获得10
7秒前
Leo完成签到,获得积分20
7秒前
Mr朱发布了新的文献求助10
7秒前
7秒前
kunkun发布了新的文献求助10
8秒前
烟花应助bxg采纳,获得10
8秒前
丫丫发布了新的文献求助10
9秒前
一独白完成签到 ,获得积分10
10秒前
10秒前
12秒前
GOD伟完成签到,获得积分10
13秒前
识途完成签到 ,获得积分10
13秒前
充电宝应助典雅的蜡烛采纳,获得10
14秒前
14秒前
LTY完成签到,获得积分10
14秒前
小铭的男仆完成签到,获得积分20
14秒前
热心的冷松完成签到,获得积分10
15秒前
勤奋的花前茶完成签到,获得积分10
16秒前
大尾巴白完成签到,获得积分10
16秒前
16秒前
16秒前
qq发布了新的文献求助10
17秒前
18秒前
蝈蝈完成签到,获得积分10
19秒前
cmq完成签到 ,获得积分10
19秒前
李健应助¥#¥-11采纳,获得10
20秒前
高分求助中
Comparative Anatomy of the Vertebrates 9th 3000
Continuum Thermodynamics and Material Modelling 3000
Production Logging: Theoretical and Interpretive Elements 2700
Les Mantodea de Guyane Insecta, Polyneoptera 1000
Structural Load Modelling and Combination for Performance and Safety Evaluation 1000
Conference Record, IAS Annual Meeting 1977 820
England and the Discovery of America, 1481-1620 600
热门求助领域 (近24小时)
化学 材料科学 生物 医学 工程类 有机化学 生物化学 物理 纳米技术 计算机科学 内科学 化学工程 复合材料 基因 遗传学 物理化学 催化作用 量子力学 光电子学 冶金
热门帖子
关注 科研通微信公众号,转发送积分 3571929
求助须知:如何正确求助?哪些是违规求助? 3142327
关于积分的说明 9446826
捐赠科研通 2843700
什么是DOI,文献DOI怎么找? 1563001
邀请新用户注册赠送积分活动 731530
科研通“疑难数据库(出版商)”最低求助积分说明 718557