Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer's Disease.
Modeling the Competition between Misfolded Aβ Conformers That Produce Distinct Types of Amyloid Pathology in Alzheimer's Disease.
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DOI：
10.3390/biom12070886
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发表时间：
2022-06-24
期刊：
影响因子：
5.5
通讯作者：
中科院分区：
文献类型：
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阿尔茨海默病（AD）的淀粉样蛋白病理学特征可广泛地分为弥漫性淀粉样蛋白或弥漫性淀粉样蛋白。纤维状淀粉样蛋白存在于核心神经炎沉积物、纤维状沉积物和血管沉积物中，并与淀粉样蛋白显示染料硫磺素-S或刚果红强烈结合。弥漫性淀粉样蛋白可表现为分散在神经胶质细胞中的束状沉积物或致密的簇状沉积物，并且即使结合淀粉样蛋白染料也很弱。在AD脑中，检测到两种类型的病理。来自AD脑或模拟AD-淀粉样变性的转基因小鼠的脑的匀浆已被用于在脆弱的宿主转基因模型中接种病理学。这些研究表明，病理可能是由不同的构象异构体或错误折叠的Aβ菌株引起的，类似于传播朊病毒。使用来自四种不同AD淀粉样变性模型的Aβ菌株，我们将病理种子注射到来自三种不同Aβ病理学的转基因宿主的新生小鼠脑中。其中两个接种源来自主要发生核心神经炎性Aβ沉积的小鼠（核心品系），而另外两个接种源来自发生弥漫性Aβ沉积的小鼠（弥漫品系）。将这些种子注射到宿主APP小鼠中，其中驻留菌株为弥漫性或核心神经炎病理。将接种匀浆注射到新生小鼠的脑中以尽可能早地开始繁殖。根据宿主中的转基因表达水平，我们表明，来自接种匀浆的错误折叠Aβ的注射菌株能够胜过APP宿主模型的驻留菌株。在系列传代实验中，扩散株似乎比核心株更容易繁殖。总的来说，我们的研究与以下观点一致：AD大脑中不同类型的Aβ病理学源于竞争填充大脑的不同Aβ构象异构体群体。
The amyloid pathology characteristic of Alzheimer’s disease (AD) can be broadly classified as either fibrillary amyloid or diffuse amyloid. Fibrillary amyloid is found in cored-neuritic deposits, fibrillar deposits, and vascular deposits, and binds strongly to the amyloid revealing dyes Thioflavin-S or Congo Red. Diffuse amyloid can appear as wispy dispersed deposits or compact tufted deposits dispersed in neuropil, and binds amyloid dyes weakly if at all. In AD brains, both types of pathology are detected. Homogenates from AD brains, or the brains of transgenic mice modeling AD-amyloidosis, have been used to seed pathology in vulnerable host transgenic models. These studies suggest that pathologies may arise from distinct conformers or strains of misfolded Aβ, similar to propagating prions. Using Aβ strains sourced from four different AD-amyloidosis models, we injected pathological seeds into the brains of newborn mice from three different transgenic hosts with distinctive Aβ pathologies. Two of the seeding sources were from mice that primarily develop cored-neuritic Aβ deposits (cored strain) while the other two seeding sources were from mice that develop diffuse Aβ deposits (diffuse strain). These seeds were injected into host APP mice in which the resident strain was either diffuse or cored-neuritic pathology. Seeding-homogenates were injected into the brains of newborn mice to initiate propagation as early as possible. Depending upon the level of transgene expression in the host, we show that the injected strains of misfolded Aβ from the seeding homogenate were able to outcompete the resident strain of the APP host model. In serial passaging experiments, it appeared that the diffuse strain was more easily propagated than the cored strain. Collectively, our studies align with the idea that different types of Aβ pathology in AD brains arise from different populations of Aβ conformers that compete to populate the brain.
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影响因子：
11
作者：
Arber C;Toombs J;Lovejoy C;Ryan NS;Paterson RW;Willumsen N;Gkanatsiou E;Portelius E;Blennow K;Heslegrave A;Schott JM;Hardy J;Lashley T;Fox NC;Zetterberg H;Wray S
通讯作者：
Wray S
影响因子：
12.7
作者：
Jaunmuktane Z;Banerjee G;Paine S;Parry-Jones A;Rudge P;Grieve J;Toma AK;Farmer SF;Mead S;Houlden H;Werring DJ;Brandner S
通讯作者：
Brandner S
影响因子：
11.2
作者：
Banerjee, Gargi;Adams, Matthew E.;Werring, David J.
通讯作者：
Werring, David J.
影响因子：
25
作者：
Lee, Ju-Hyun;Yang, Dun-Sheng;Goulbourne, Chris N.;Im, Eunju;Stavrides, Philip;Pensalfini, Anna;Chan, Han;Bouchet-Marquis, Cedric;Bleiwas, Cynthia;Berg, Martin J.;Huo, Chunfeng;Peddy, James;Pawlik, Monika;Levy, Efrat;Rao, Mala;Staufenbiel, Mathias;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
DOI：
10.1073/pnas.162228299
发表时间：
2002-08-06
影响因子：
11.1
作者：
DeMattos, RB;O'dell, MA;Holtzman, DM
通讯作者：
Holtzman, DM