Acta Neuropathologica: MAP kinase p38 reduces tau-mediated late memory defects.

Alzheimer's disease (AD) is the most common form of dementia, characterized by extracellular plaques containing amyloid β (A beta) and intracellular tangles made up of neuron tau proteins.
Although our understanding of disease mechanisms has increased, there are no significant benefits in large clinical trials in treating AD by targeting A-beta or its processing from amyloid pregenital proteins (APPS).
, recent explorations of disease mechanisms and therapeutic development have focused mainly on tau.
aspects of AD can be modeled in mouse models where human APP is expressed in neurons.
-modified mice with APP showed the aggressive deposition of amyloid plaques.
we have previously shown that bit-specific thau phosphorylation inhibits toxic signals induced by amyloid protein β (A beta).
synapses, a silk splitogen activation protein (MAP) kinase p38 gamma mediates the point-specific phosphatization of tau on suline-205 (T205).
using gene therapy, we used this neuroproteging mechanism to improve the memory of two A-beta-dependent AD mouse models during the late memory deficit phase.
increase in the activity of the synaptic post-kinase p38 in Tau reduced memory defects in the symptomatic A-beta-induced AD model.
recombination experiments with wild human tau or phosphorylation defect tau T205A showed that T205 modification was essential for the downstream effects of p38 gamma, which prevents memory impairment in APP-modified mice.
addition, genome editing of T205 cophers in mouse Mapt gene showed that the one-sided chain in endogeneau had a key regulatory effect on memory defects in APP-modified AD mice.
in the model of tau genetically modified mice expressing non-pathogenic tau, the protective effect of p38 gamma activity was eliminated by the absence of the gene p38, making tau toxic and causing impaired memory function when human ata is missing.
, we believe that regulating the activity of neuron p38 is an innitable tau-dependent treatment that enhances impaired cognition in patients with advanced dementia.
: The method of purifying synapses from cortic tissue is described earlier.
simply put, homogenize in a 30 mg tissue/ml iced sucrose buffer using a pre-cooled homogenizer.
the particles are re-suspended in the sucrose buffer and re-centrifuged (1400g, 10min, 4C) after the homogeneity is removed by centrifugation (1400g, 10min, 4C).
the liquid, centrifuge again, and rotate the upper liquid (total brain slurry) at 13800 g at 4 degrees C for 10 minutes.
the particles in a sucrose buffer, layered and centrifuged at 45,000g for 45 minutes.
re-suspended Pellet in 5 per cent Ficoll, layered on 13 per cent Ficoll, and centrifuged at 45,000g for 45 minutes.
collection interface (synapses), diluted in 5% Ficoll, centrifuged at 45 degrees C, collected semen (non-synapses) and washed in pH8 buffers and resuscued in pH8 buffers, thus forming a coarse synaptic cleavage.
determine the concentration of proteins in different parts before preparing samples for protein imprinting.
above, our results show that tau phosphatization, which is specific to the target bits by synaptic post-kinase p38, is a potential treatment that can reduce memory impairment in existing A-beta-induced AD mouse models.
it is safe to increase the activity of p38 gamma through gene therapy vectors and does not promote tau pathological changes, including at high tau levels.
, we found that p38 gamma limits tau-dependent memory damage in the absence of high A-beta levels, supporting the direct effects of p38 gamma on tau toxicity.
Ittner, A., Asih, P.R., Tan, A.R.P. et al. Reduction of advanced tau-mediated memory reds by the MAP kinase p38. Acta Neuropathol 140, 279-294 (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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