Introduction to Amyloid Beta


Posted May 23, 2019 by Bonnibelle

The molecular weight of amyloid beta (Aβ) is about 4 kDa. It is hydrolyzed by beta-amyloid precursor protein (APP) and secreted by cells.

 
There are some antibodies:

82e1 antibody: The anti-amyloid beta is a monoclonal antibody capable of recognizing amyloid β while not recognizing amyloid β precursor protein. The antibody can be used in the treatment of Alzheimer's disease.

37h: The anti-amyloid antibodies refer to amyloid beta specific scFv antibody fragment as well as the single domain antibody fragment, the specific antibody fragments can be used for treating or inhibiting Alzheimer's disease.

13c3: The anti-amyloid beta antibody specifically binds the protofibril form of amyloid beta protein and can be used for therapeutic and prophylactic treatment of Alzheimer's disease.

Aducanumab: Recombinant human monoclonal antibody expressed in CHO binding to human amyloid beta. Aducanumab is a human monoclonal antibody designed for the treatment of Alzheimer's disease.

So, today let us learn some knowledge about amyloid beta.

What is the amyloid beta?

 

The molecular weight of amyloid beta (Aβ) is about 4 kDa. It is hydrolyzed by beta-amyloid precursor protein (APP) and secreted by cells. It has a strong neurotoxic effect after precipitation and accumulation of cell matrix. It can be produced by a variety of cells, circulating in the blood, cerebrospinal fluid and interstitial fluid, most of which bind to chaperone molecules, and a few exist in a free state.

The most common subtypes of Aβ in human body are Aβ1-40 and Aβ1-42. In human cerebrospinal fluid and blood, the content of Aβ1-40 is 10 times and 1.5 times higher than that of Aβ1-42, respectively. Aβ1-42 is more toxic and easier to aggregate, thus forming the core of Aβ precipitation and triggering neurotoxicity.

Production principle

Aβ is produced by hydrolysis of APP by beta-and gamma-secretase. APP is a membrane protein widely distributed in various tissues and concentrated in the synaptic site of neurons. The A beta fragment is located in its transmembrane region. Beta-secretase first splits APP at the beta site into beta-N-terminal fragments (sAPP-β) and beta-C-terminal fragments. Then gamma-secretase hydrolyzes near the N-terminal transmembrane region of the beta-C-terminal fragment and releases a beta-peptide composed of 39-43 amino acids. This process is called the amyloid degradation pathway of APP. The non-amyloid degradation pathway of APP is mediated by A-and gamma-secretase. The productivity of Aβ depends mainly on the subcellular localization of APP and its hydrolase. In the stable state, alpha-secretase mainly distributes on the cell membrane, while beta-secretase mainly locates in the tans-Golgi network (TGN) and connotative body of Golgi body. Gamma-secretase is widely distributed in the cell membrane and various organelles. APP is synthesized in the endoplasmic reticulum and transformed into the permanent site of TGN after processing modification of Golgi complex, which is also one of the main producing sites of Aβ. APP can be degraded by beta-and gamma-secretase to produce Abeta when TGN is retained. Undegraded full-length APP can be transported to the surface of cell membrane through secretory vesicles produced by TGN, and then non-amyloid degradation or endocytosis of vesicles encapsulated by network proteins is mediated by the alpha-secretase located therein, and then hydrolyzed by beta-and gamma-secretases distributed therein to produce Aβ or a small part of it is recycled to the surface of cell membrane.

The role of Aβ

The neurotoxicity of Aβ

The neurotoxicity of Aβ plays a major role in the progression of Alzheimer's disease. In 1991, research injected Aβ into the cerebral cortex of rats or monkeys. Tissue necrosis, loss of peripheral neurons and hyperplasia of nerve keratin were found at the injection site, which was significantly correlated with the dose. The toxic effect of Aβ on nervous system is that amyloidosis of blood vessel wall directly leads to vascular sclerosis, poor elasticity, even easy to rupture or thrombosis, and induces premature apoptosis of nerve cells. Animal experiments have shown that the effect of Aβ on neurons is related to their state. Dissolved Aβ promotes neurite growth and improves neuron survival rate in a short time. Deposited Aβ has the opposite effect on neurons, causing neurodegeneration and neurodegeneration similar to Alzheimer's disease. The most significant changes occur in the aging mammalian brain.

The effect on vascular morphology and function

Aβ first deposits in the basement membrane of the outer layer of the blood vessel and then infiltrates into the smooth muscle cell layer. The deposition of Aβ reduced the adhesion of SMCs to the basement membrane. The middle layer of blood vessel was replaced by Aβ, and the smooth muscle cells degenerated. Researchers have found that Aβ is deposited in the basement membrane of capillaries and protrudes into the nerve felt in a plate shape. A beta promotes the deposition of perivascular fibers, leading to amyloid angiopathy. There are two possible mechanisms.

Reducing the expression of fibroblast growth factor 2

The effect of Aβ on vascular endothelial cells via fibroblast growth factor 2 pathway is through autocrine/paracrine pathway. Aβ interacts with the membrane receptor of fibroblast growth factor-2 to block the role of fibroblast growth factor-2 axis.

The point mutation of APP results in the variation of amino acids at position 21-23 of Aβ. These mutants are closely related to the different genetic phenotypes of amyloid angiopathy, the degree of cerebral vascular tropism, the remodeling of damaged microvessels and vascular proliferation.

To sum up, Aβ is one of the starting factors and key links in the pathogenesis of AD. At present, some progress has been made in the prevention and treatment of AD by clearing the Aβ pathway. With the in-depth study of Aβ, therapeutic drugs targeting Aβ will emerge continuously, bringing good news to AD patients.
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Issued By https://www.creativebiolabs.net
Country United States
Categories Biotech
Last Updated May 23, 2019