硫黄素 S 阳性淀粉样沉积物在转基因小鼠和阿尔茨海默病中的神经毒性作用。
Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.
作者信息
Urbanc B, Cruz L, Le R, Sanders J, Ashe K Hsiao, Duff K, Stanley H E, Irizarry M C, Hyman B T
机构信息
Center for Polymer Studies and Department of Physics, Boston University, Boston, MA 02215, USA.
出版信息
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):13990-5. doi: 10.1073/pnas.222433299. Epub 2002 Oct 9.
Abstract
Despite extensive deposition of putatively neurotoxic amyloid-beta (Abeta) protein in the brain, it has not been possible to demonstrate an association of Abeta deposits with neuronal loss in Alzheimer's disease (AD), and neuronal loss is minimal in transgenic mouse models of AD. Using triple immunostaining confocal microscopy and analyzing the images with the cross-correlation density map method from statistical physics, we directly compared Abeta deposition, Abeta morphology, and neuronal architecture. We found dramatic, focal neuronal toxicity associated primarily with thioflavin S-positive fibrillar Abeta deposits in both AD and PSAPP mice. These results, along with computer simulations, suggest that Abeta develops neurotoxic properties in vivo when it adopts a fibrillar beta-pleated sheet conformation.
摘要
尽管在大脑中存在大量推测具有神经毒性的β淀粉样蛋白（Aβ）沉积，但在阿尔茨海默病（AD）中，尚未证实Aβ沉积与神经元丢失之间存在关联，并且在AD转基因小鼠模型中神经元丢失极少。我们使用三重免疫染色共聚焦显微镜，并采用统计物理学中的互相关密度图方法对图像进行分析，直接比较了Aβ沉积、Aβ形态和神经元结构。我们发现，在AD和PSAPP小鼠中，显著的局灶性神经元毒性主要与硫黄素S阳性的纤维状Aβ沉积有关。这些结果以及计算机模拟表明，当Aβ采用纤维状β折叠片构象时，它在体内会产生神经毒性特性。
相似文献
1
Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):13990-5. doi: 10.1073/pnas.222433299. Epub 2002 Oct 9.
2
Tg-SwDI transgenic mice exhibit novel alterations in AbetaPP processing, Abeta degradation, and resilient amyloid angiopathy.
Am J Pathol. 2008 Aug;173(2):483-93. doi: 10.2353/ajpath.2008.071191. Epub 2008 Jul 3.
3
Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss.
Am J Pathol. 2000 Jul;157(1):331-9. doi: 10.1016/s0002-9440(10)64544-0.
4
Mostly separate distributions of CLAC- versus Abeta40- or thioflavin S-reactivities in senile plaques reveal two distinct subpopulations of beta-amyloid deposits.
Am J Pathol. 2004 Jul;165(1):273-81. doi: 10.1016/s0002-9440(10)63295-6.
5
Impact of CRFR1 Ablation on Amyloid-β Production and Accumulation in a Mouse Model of Alzheimer's Disease.
J Alzheimers Dis. 2015;45(4):1175-84. doi: 10.3233/JAD-142844.
6
Inflammatory responses to amyloidosis in a transgenic mouse model of Alzheimer's disease.
Am J Pathol. 2001 Apr;158(4):1345-54. doi: 10.1016/S0002-9440(10)64085-0.
7
Delineating Amyloid Plaque Associated Neuronal Sphingolipids in Transgenic Alzheimer's Disease Mice (tgArcSwe) Using MALDI Imaging Mass Spectrometry.
ACS Chem Neurosci. 2017 Feb 15;8(2):347-355. doi: 10.1021/acschemneuro.6b00391. Epub 2017 Jan 10.
8
Diffuse amyloid deposition, but not plaque number, is reduced in amyloid precursor protein/presenilin 1 double-transgenic mice by pathway lesions.
Neuroscience. 2003;119(4):1185-97. doi: 10.1016/s0306-4522(03)00215-x.
9
Beta-amyloid deposition and functional impairment in the retina of the APPswe/PS1DeltaE9 transgenic mouse model of Alzheimer's disease.
Invest Ophthalmol Vis Sci. 2009 Feb;50(2):793-800. doi: 10.1167/iovs.08-2384. Epub 2008 Sep 12.
10
Abundance of Aβ₅-x like immunoreactivity in transgenic 5XFAD, APP/PS1KI and 3xTG mice, sporadic and familial Alzheimer's disease.
Mol Neurodegener. 2014 Apr 2;9:13. doi: 10.1186/1750-1326-9-13.
引用本文的文献
1
Stilbenes Against Alzheimer's Disease: A Comprehensive Review of Preclinical Studies of Natural and Synthetic Compounds Combined with the Contributions of Developed Nanodrug Delivery Systems.
Molecules. 2025 Apr 29;30(9):1982. doi: 10.3390/molecules30091982.
2
Interleukin-6 deficiency reduces neuroinflammation by inhibiting the STAT3-cGAS-STING pathway in Alzheimer's disease mice.
J Neuroinflammation. 2024 Nov 1;21(1):282. doi: 10.1186/s12974-024-03277-3.
3
Carotenoid Supplementation for Alleviating the Symptoms of Alzheimer's Disease.
Int J Mol Sci. 2024 Aug 18;25(16):8982. doi: 10.3390/ijms25168982.
4
Monoclonal Antibody Therapy in Alzheimer's Disease.
Pharmaceutics. 2023 Dec 29;16(1):60. doi: 10.3390/pharmaceutics16010060.
5
Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer's pathology.
Transl Neurodegener. 2024 Jan 4;13(1):2. doi: 10.1186/s40035-023-00393-7.
6
Physiological Mechanisms Inherent to Diabetes Involved in the Development of Dementia: Alzheimer's Disease.
Neurol Int. 2023 Oct 10;15(4):1253-1272. doi: 10.3390/neurolint15040079.
7
Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease.
Alzheimers Dement. 2024 Jan;20(1):74-90. doi: 10.1002/alz.13387. Epub 2023 Jul 17.
8
Distinct Transcriptomic Responses to Aβ plaques, Neurofibrillary Tangles, and in Alzheimer's Disease.
bioRxiv. 2023 Mar 21:2023.03.20.533303. doi: 10.1101/2023.03.20.533303.
9
Post-mortem brain histological examination in the substantia nigra and subthalamic nucleus in Parkinson's disease following deep brain stimulation.
Front Neurosci. 2022 Sep 14;16:948523. doi: 10.3389/fnins.2022.948523. eCollection 2022.
10
Excited-State Intramolecular Hydrogen Transfer of Compact Molecules Controls Amyloid Aggregation Profiles.
JACS Au. 2022 Aug 11;2(9):2001-2012. doi: 10.1021/jacsau.2c00281. eCollection 2022 Sep 26.
本文引用的文献
1
Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis.
J Neurosci. 2002 Apr 15;22(8):3234-43. doi: 10.1523/JNEUROSCI.22-08-03234.2002.
2
Formation of neurofibrillary tangles in P301l tau transgenic mice induced by Abeta 42 fibrils.
Science. 2001 Aug 24;293(5534):1491-5. doi: 10.1126/science.1062097.
3
Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP.
Science. 2001 Aug 24;293(5534):1487-91. doi: 10.1126/science.1058189.
4
Plaque-induced abnormalities in neurite geometry in transgenic models of Alzheimer disease: implications for neural system disruption.
J Neuropathol Exp Neurol. 2001 Aug;60(8):753-8. doi: 10.1093/jnen/60.8.753.
5
Neuropathology of mice carrying mutant APP(swe) and/or PS1(M146L) transgenes: alterations in the p75(NTR) cholinergic basal forebrain septohippocampal pathway.
Exp Neurol. 2001 Aug;170(2):227-43. doi: 10.1006/exnr.2001.7710.
6
Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimer's disease.
Neuroscience. 2001;104(3):609-13. doi: 10.1016/s0306-4522(01)00115-4.
7
Age-related amyloid beta deposition in transgenic mice overexpressing both Alzheimer mutant presenilin 1 and amyloid beta precursor protein Swedish mutant is not associated with global neuronal loss.
Am J Pathol. 2000 Jul;157(1):331-9. doi: 10.1016/s0002-9440(10)64544-0.
8
Description of microcolumnar ensembles in association cortex and their disruption in Alzheimer and Lewy body dementias.
Proc Natl Acad Sci U S A. 2000 May 9;97(10):5039-43. doi: 10.1073/pnas.060009897.
9
Amyloid beta interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease.
Nat Neurosci. 2000 May;3(5):460-4. doi: 10.1038/74833.
10
The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors.
Brain. 1999 Sep;122 ( Pt 9):1709-19. doi: 10.1093/brain/122.9.1709.
Zotero 插件