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Amyloid beta (A4) precursor protein degradation products of the pathogenic role of Alzheimer's disease research progress
APP is a transmembrane glycoprotein widely present in various tissues, containing a longer fragment of the extracellular amino-terminal (N-terminal) and short segments of the intracellular carboxy-terminal (C-terminal), and its encoding gene is located on the first human 21 chromosome 21q21.2, the transcription, translation and processing mainly expressed in the formation of three kinds with different length of the peptide chain isoforms, APP695, APP751 and APP770. Compared with the other two isoforms, APP695 lacks the Kunitz protease inhibitor (KPI) region outside the cell. Neurons expressing APP695 subtypes in the cerebral cortex of APP695, APP751 and APP770 mRNA ratio of 20:10:1. The function of APP may be: (1) G protein-coupled receptor-like role to participate in transmembrane signal transduction process. (2) to promote cell adhesion, cell shape remodeling and neural development. (3) to promote the occurrence of synaptic structure, and enhance synaptic plasticity and synaptic transmission. At APP695 subtype, with the majority of membrane proteins, transmembrane proteins of the orphan receptor characteristics, it is easier by complex protein hydrolysis pathway cracking of varying sizes peptide fragments, including a relatively long extracellular amino terminal peptide fragment, the smaller the A beta protein (the main component of senile plaques) and a variety of sizes ranging from APP intracellular domain (AICD). The traditional view is that the APP degradation by two ways. Α-secretase pathway: (1), also known as non-amyloid formation routes. Followed by the alpha, gamma secretase cutting, resulting in the exocytosis of APP (s APP alpha), P3 ~ 40 (A beta 17 or A beta 17 ~ 42) fragment and APP intracellular domain fragment. The role of the α-secretase enzyme sites in the region of A beta structure, it does not produce a complete A-beta fragment. (2) β-secretase pathway: also known as amyloid formation routes. Cutting followed by the β and γ-secretase enzyme, resulting in extracellular s APP beta, A beta (A beta 40 and A beta 42) fragment and APP intracellular domain fragment. It is generally believed that these two degradation pathways exist, α and β-secretase enzyme state of relative equilibrium and there is competition in the role of the substrate.Physiological conditions, the main enzymatic pathways of α secretion, while pathological conditions, while β-secretase pathway-based, resulting in excess of A beta 40 and A beta 42, the formation of A beta deposition as the core of senile plaques and disease.But so far to regulate these two selective digestion of APP specific mechanism remains unclear.
The traditional view is that the extracellular A-beta deposition play an important role in the pathogenesis of Alzheimer's disease. However, Gouras et al in patients with mild cognitive impairment (MCI) hippocampus and entorhinal cortex region of neurons found in A beta accumulation, and Mori and also with Down syndrome (Down syndrome) in patients with brain tissue similar change. Tips, intracellular A beta aggregation before extracellular A beta deposition in Alzheimer's disease process. These inferences and the transgenic mouse model to obtain the research results. In vitro experiments and mouse neurons A beta positioning study are confirmed, a variety of pathological effects of intracellular A beta in Alzheimer's disease in the pathological process, including through the inhibition of proteasome activity and the promotion of tau protein aggregation in the mitochondria progressive aggregation inhibition of the respiratory chain enzyme Erzhi hypoxia, caused by calcium metabolic disorders and inhibition of long duration action potential, leading to memory and cognitive dysfunction. This shows that A beta may also accumulate in cells and play an important role in the early onset of Alzheimer's disease. However, the conclusion still need the same evidence in order to further confirm that in the brain tissue of Alzheimer patients.
2 posts • Page 1 of 1
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