Acta Neuropathologica: The accumulation of end fragments of amyloid preloom protein C triggers mitochondrial structure, function, and filamentation defects in Alzheimer's models and the human brain.

Some recent evidence suggests that C-end fragments (APP-CTFs) derived from amyloid prescrotes proteins may be associated with the triggering of the pathogenesies of Alzheimer's disease (AD).
in the mitochondrials is considered an early event in AD development.
, the specific contribution of APP-CTFs to mitochondrial structure, function and silk splitting defects has yet to be confirmed.
Here, we demonstrate that in neuroblastoma SH-SY5Y cells, the expression of APP Swedish mutations or β-secretase-derived APP-CTF fragments (C99) is combined with β and γ-secretase inhibition, and that the accumulation of APP-CTF is independent of excessive mitochondrial morphological changes triggered by A beta, which is associated with mitochondrial active oxygen enhancement.
App-CTFs accumulation also causes basic silk splitting failure, which is manifested in the conversion enhancement of LC3, the accumulation of LC3-I and/or LC3-II, non-degradation of SQSTM1/p62, inconsistent collection of Parkin and PINK1 in mitochondrials, increased levels of membrane and substring mitochondrial proteins, and insufficient mitochondrial and lysosome fusion.
We also confirmed that the accumulation of APP-CTFs had a impaired effect on the function of silk division in young 3xTgAD genetically modified mice treated with γ-secretase inhibitors, as well as in adeno-related virus C99 injected mice with morphological mitochondrial changes and fundamental silk division.
2xTgAD and 3xTgAD older mice showed that, in addition to APP-CTFs, A-beta had an additional effect on the activation of late-stage silk division.
, we reported that mitochondrial accumulation of APP-ctf in the human post-mortem AD brain was associated with molecular characteristics of silky splice failure.
: Prepare total protein extract using lysate buffers (50 mM Tris pH 8, 10% glycerin, 200 mM NaCl, 0.5% Nonidet p-40, and 0.1 mM EDTA) with protease inhibitors added.
the mitochondrial portion using a mixture of added protease inhibitors (250 mM D-Glycol, 5 mM HEPES pH 7.4, 0.5 mM EGTA, and 0.1% BSA).
after freezing on ice for 20 minutes and frequently tapping, cells, mouse brains, or anatomic sea otters were crushed 120 times by glass homogenizers, centrifuged at 1500×g, 4 degrees C to remove unrecrupted cells and nuclei.
collecting the liquid as the total fraction, the other part at 4 degrees C at 10000 × g centrifugation for 10 minutes to precipitate mitochondrial fractions, it suspended in a separation buffer with protease inhibitors added.
full-length APP, APP-CTFs, and A-beta are separated on 16.5% trisine-SDS-PAGE and transferred to the cellulose nitrate membrane.
the film in PBS, saturate it in TBS, 5% skimmed milk, and incubate overnight with specific antibodies.
the rest of the proteins were separated by standard procedures for SDS-PAGE.
above, mitochondrial steady-state defects play a key role in the pathogenesis of AD, so targeting mitochondrial dysfunction and/or devouration by inhibiting the accumulation of early APP-CTFs may be AD-related therapeutic interventions.
Vaillant-Beuchot, L., Mary, A., Pardossi-Piquard, R. et al. Edgion o amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. Acta Neuropathol (2020). MedSci Original Source: MedSci Original Copyright Notice: All text, images and audio and video materials on this website that indicate "Source: Mets Medicine" or "Source: MedSci Original" are owned by Mets Medicine and are not authorized to be reproduced by any media, website or individual, and are authorized to be reproduced with the words "Source: Mets Medicine".
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