Advances in the study of amyloid beta peptide

Alzheimer's disease (AD) is a degenerative disease of the central nervous system mainly caused by cognitive impairment and memory impairment in old age. In western countries, AD has become the fourth killer threatening human health after heart disease, tumor and stroke. Beta amyloid peptide (A beta) can be selectively deposited early in the senile plaques of patients with alzheimer's disease (AD). It is A common pathway for various causes to induce AD and A key factor in the formation and development of AD. The occurrence of A predates pathological changes and clinical symptoms such as neurofibrillary tangles and axonal deficiency. In vitro studies by Yankner et al. showed that high concentrations of A have toxic effects on cultured nerve cells, inhibiting their survival and axonal growth. In this paper, the research progress of A in recent years is summarized as follows.

1 A structure

The most prominent feature in AD patients is the formation of insoluble amyloid plaques (senile plaques), with some patients presenting with cholinergic receptor inactivation and nerve fiber tangles. Senile plaques are formed by the aggregation of beta-amyloid peptide (A) outside of brain nerve cells. A consists of 39-43 amino acids, small peptides with A folded configuration and A length of 4KD. Approximately 90% are A 1-40, and the other 10% are A 1-42 and A 1-43, which are highly fibrotic and precipitate selectively early in senile plaques in patients with AD. The precipitated A is neurotoxic.

The hydrophobic region of A 1-42 was composed of 10 amino acid residues 33-42 and 5 amino acids 17-21 at the end of A 1-42c (the first amino acid at the N end of A was numbered as 1). It is possible to form a -folded conformation for residues of 28-42 amino acids, while it is also possible to form a -folded conformation for residues of 9-21 amino acids. C-terminal Val40Ile41Ala42 these three amino acid residues play a stable role in the formation of beta-folding, which is beneficial to the formation of beta-folding. The N ends of A 1-42 are hydrophilic and, depending on the solution conditions, can form conformations of A -helix, random helix, or A -fold. The A 1-42 conformation is favorable for A 1-42 aggregation.

Formation of 2 A

AB, which aggregates outside brain nerve cells to form senile plaques, is produced by hydrolysis of transmembrane protein (-amyloid precursor protein, APP). APP is a transmembrane glycoprotein, which is divided into three parts: extramembrane region, transmembrane region and intramembrane region. A consists of 28 amino acids outside the APP cell and 12 amino acids in the transmembrane portion. A is located in the hydrophobic part of the APP, with strong aggregation and easy to form extremely insoluble precipitates. Studies have shown that at least three proteolytic enzymes, alpha - secretase, beta - secretase and gamma - secretase, are involved in the metabolism of APP. APP hydrolysis mainly includes two non-amyloid peptide-derived pathways (structural secretion) and amyloid peptide-derived pathways. Under physiological conditions, most apps are cleaved into soluble APP peptides by alpha - secretase, and APP peptides are further cleaved by gamma - secretase to produce P3, which is the former pathway. The latter pathway is cleaved into A in the cytoplasmic lysozyme by continuous action of -secretase and -secretase.

3 A neurotoxicity

A is neurotoxic and its toxicity plays A major role in the progression of AD [1]. In 1992, Kowall reported that animal brain perfusion showed focal necrosis, neuronal loss and glial hyperplasia at the injection site. Chinese scholar gao quwen et al. also confirmed in rat experiments that the toxic effects of A on the nervous system: amyloidosis of the blood vessel wall directly leads to vascular sclerosis, poor elasticity, and even easy rupture or thrombosis, and can induce premature apoptosis of nerve cells. In recent years found that there are three can combine with A beta specific receptor, the receptor protein glycosylation end-products (RAGE), scavenger receptor (SR) and serine protease inhibitors enzyme complex receptor (SEC - R), A beta, and these three receptors, can be directly or indirectly activated microglia and astrocytes, release complement, cell factors, free radicals and cell toxic substances, etc.

4 A neurotoxic mechanisms of action

4. 1 destruction of calcium homeostasis

Intracellular Ca2+ homeostasis is important for the normal physiological function of cells. When the Ca2+ homeostasis is disturbed, the signal transduction system will be changed. It can form a tiny tunnel on the cell membrane or destroy the K channel, leading to a large amount of external Ca2+ internal flow, making the intracellular Ca2+ overload. Study found that nerve cells cultured in vitro, A beta can induce the inflow Ca2 +, Ca2 + homeostasis disorders, intracellular Ca2 + overload will cause serious consequences, on the one hand injury of the oxidative phosphorylation, dependence on the other hand lead to calcium paranormal activities of enzymes, resulting in insufficient cells of energy depletion, even damage cellular structure and function, affects the long cheng synaptic strengthening effect, synaptic plasticity is reduced, at the same time, the intracellular Ca2 + overload also promote the lipid peroxidation and the formation of free radicals, increase the cell predisposition to oxidative stress and excitability toxicity, fuel cell damage. In turn, the disorder of calcium ions can increase the sensitivity of cells to APP and hinder APP transport and shear process, thus forming a vicious cycle.

4. 2. Effects of oxygen stress

When APP ruptured A, free radicals were released to peroxide the lipid membrane of the nerve cells. Under electron microscopy, the destruction of the membrane structure and the rapid disintegration of the membrane can be clearly seen when A is acted on the primary cultured neurons in high concentration. In addition. By activating the end product receptor (RAGE) of progressive glycosylation, glial cells produce free radicals, such as increased expression of NO and inflammatory factors il-1 and TNF, which are released to the extracellular environment and act on the c-fos receptor of adjacent microglial cells, inducing increased expression of cell scavenger receptor and ApoE4. In addition, m-csf can activate the proliferation and migration of microglia to produce higher levels of reactive oxygen species, which may lead to neuritis plaques. As a result, the function of reactive oxygen can cause neuron loss and even death. A 42 can damage the antioxidant system in vivo. It was found that continuous injection of A 422 weeks reduced the antioxidant superoxide dismutase (sod) and glutamate glycine (ggan) in the hippocampus, cortex and plasma of the brain. Antioxidant (V-E, etc.) can prevent learning and memory impairment in rats.

4. 3. Cholinergic nerve damage

Studies have shown that A beta can cause cholinergic nerve damage, its mechanism is: (1) promote the choline neurons release to the outside of the cell, cell depletion bladder alkali, thereby reducing the Ach synthesis, A beta can also activate the tau protein kinase 1, make the pyruvate dehydrogenase phosphorylation, thus reducing the pyruvate is converted into acetyl coenzyme A, and acetyl coa is raw material for the synthesis of Ach, thus reducing the Ach synthesis; (2) inhibit the release of neuroendogenous Ach; (3) inhibit the uptake of high-affinity choline by cells; (4) promote the opening of potassium ion channels in the choline nerve cell membrane, promote K+ outflow, and lead to cell death; (5) increased NMDA receptor response to glutamic acid, resulting in excitatory toxicity; (6) A beta on L voltage dependent calcium channel, increase the intracellular Ca2 + concentration, can lead to abnormal expression of AchE [; (7) damage M and G protein coupled receptor, excited after blocking M receptor signal transduction, this effect may be produced by A beta oxidation damage; (8) AchE degradation at A slower pace. Foreign study found that neuroblastoma cells in vitro culture, A beta can make AchE expression increases, its degradation speed is slow, rather than synthetic increase. Adherent cells increased 30-40%, Non-adherent cells increased by 100% or more [13]. (2) and (3) were found only in the cortical and hippocampal regions associated with learning and memory.

4. 4 inflammatory immune function

A can cause the proliferation of glial cells in the nucleus, hippocampus and cortex of Meynert, which is dominated by microglial cells, followed by astrocytes, microglial cells aggregation and phagocytosis of degenerated nerve cells, and hyperactive microglial cells aggregation around blood vessels. In vitro experiments, A induces the expression of A variety of cytokines such as il-1, il-6 and INF- in microglia cells. Il-1 and il-6 can increase the synthesis of APP, leading to overexpression of APP, thus forming A vicious cycle. Il-6 has almost no significant damage to neurons cultured in vitro, but in the presence of A and NMDA, the damage of il-6 to neurons is much greater than that in the separate and combined treatment groups of A and NMDA. Cytokines can cause inflammatory reactions. Studies have shown that non-steroidal anti-inflammatory drugs (such as indomectin) can reduce the incidence of AD. Senile plaques cannot directly cause learning and memory disorders, but they may trigger inflammatory reactions and have harmful effects on synaptic function and learning and memory. On the other hand, TNF- can cause cell death, resulting in memory loss and cognitive impairment. In patients with AD, antibodies to A are increased and the humoral immune response is enhanced. Promotes neuron degeneration.

4. Apoptosis of nerve cells

In vitro culture and transgenic mice, A can induce apoptosis of nerve cells by :(1) acting through Caspase(cysteine aspartate specific protease). (2) A also has an effect on the expression of apoptotic genes. A 40/42 down-regulates the anti-apoptotic protein bcl-2, but A 42 reduces bcl-2 much faster than that. Meanwhile, A 42 also up-regulates the expression of pro-apoptotic protein Bax. Bax, on the other hand, can be inserted into the mitochondria to form channels and cause the overflow of cytochrome C into the cytoplasm. Cytochrome C can activate the Caspase cascade and cause cell apoptosis. Overproduction could lead to A beta APP not reduce amyloid metabolic pathway, therefore produce less soluble APP, because it reduces, to increase the sensitivity of the nerve cells for A lot of damage, the APP mutants and PS and PS - 1-2 May combine with other proteins and cause cell death, such as huntingtinhe and SOD can not normally interact with other proteins, leading to cell death. [19].

5 treatment pathways for AD

Although there are many theories about the pathogenesis of AD, more and more studies have shown that the formation and deposition of aggregates in brain tissue may play a key role in the occurrence and development of AD. Therefore, targeting toxic effects is a promising research hotspot in the treatment of AD. The main methods used now are :(1) inhibition of the generation of A. Inhibiting the activity of and -secretase or altering the metabolic pathway of APP to slow or reduce the production of A, thereby reducing the concentration of A in the brain and preventing its aggregation. (2) inhibition of A aggregation. Soto et al. used amino acid substitution method to make A not form A -folding structure and inhibit its aggregation. Some compounds, such as rifampicin, benzofuran, nicotine, Congo red and quaternary ammonium salt, have similar inhibitory effects. (3) inhibit the neurotoxic effects of A and accelerate its degradation and clearance. A can cause oxidative and inflammatory reactions that lead to neuron loss and cognitive impairment. Epidemiological investigation shows that the use of antioxidants, anti-inflammatory drugs have a certain effect. In recent years, scientists have done A lot of research work and made achievements in the treatment of AD, but at present, people's understanding of the neurotoxicity of A and the mechanism of its removal and degradation is not very clear, and the research on AD is limited to make breakthroughs in the treatment of AD. Further studies on the pathogenesis of AD are needed.