Something about Amyloid Beta-Protein

  • There are some antibodies to amyloid beta-protein:

    1. Crenezumab

    Recombinant monoclonal antibody to Aβ. Crenezumab is a humanized monoclonal antibody against human 1-40 and 1-42 Beta amyloid, which is being investigated as a treatment of Alzheimer's disease.  

    1. Gantenerumab

    Recombinant monoclonal antibody to Aβ. Gantenerumab is a monoclonal antibody for the treatment of Alzheimer's disease. A phase I clinical trial has been conducted Gantenerumab is currently being evaluated in a prodromal Alzheimer's disease population in the Scarlet Road study, a global phase II study of approximately 360 subjects in 100 centers in 15 countries.  

    1. Solanezumab

    Recombinant monoclonal antibody to Aβ. Solanezumab binds to the amyloid-β peptides that make up the protein plaques seen in the brains of people with the disease.  

    These antibodies are related to Aβ, so what is Aβ?

     

    Figure1. Aβ in the brain

    The molecular weight of amyloid beta-protein (Aβ) is about 4 kD. 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. Under normal physiological conditions, Aβ can be detected in blood and cerebrospinal fluid. The main way of clearing Aβ is through transport mechanism and enzymatic degradation. The transport of Aβ, soluble Aβ, is slowly removed from the brain through the circulation of brain interstitial fluid (ISF) - cerebrospinal fluid (CSF) - blood. Another type of transport, mediated by receptors, is accomplished by transporting Aβ across the blood-brain barrier (BBB).

    Molecular structural characteristics of APP and Aβ

    APP is a selective splint-like semi-monohelical transmembrane protein. The long allele contains 770 amino acids and consists of two exons, which can be expressed in most tissues. Short alleles contain 695 amino acids, mainly expressed in brain tissue. In addition, there are several rare alleles. Aβ is a fragment produced by the cleavage of the 672 to 711 residues of APP.  mainly consists of two molecules, Aβ 40 and Aβ 42, or 39 to 43 amino acids. Aβ 42 is more hydrophobic and aggregated than Aβ 40.

    The metabolic process of Aβ

    In normal physiological state, Aβ can be detected in blood and cerebrospinal fluid. The concentration of Aβ is mainly affected by the following factors: ①metabolic regulation of APP;②clearance of Aβ and transport across blood-brain barrier;③ degradation of Aβ protease;④oligomerization of Aβ; and ⑤separation and binding ability of Aβ with proteins . Aβ can be degraded by a variety of peptidases, the most important of which are two zinc-dependent metalloproteinases: enkephalin and insulin-degrading enzymes. The clearance of Aβ also depends on the body's immune mechanism. Peripheral Aβ antibodies can be transported to the brain through immersion, and combine with Aβ to form immune complexes, which activate microglia to clear the deposition of Aβ. In addition, the Aβ antibody/Aβ immune complex can also be transported to peripheral blood through Fc receptor across the blood-brain barrier. The interaction between Aβ and its binding protein can also regulate its metabolic process, reduce the aggregation of Aβ and promote its clearance and degradation. The natural properties of Abβ enable it to bind to a variety of proteins. For example, Slrp1, albumin, alpha 1 anti-chymotrypsin, serum amyloid protein P, lipoprotein and so on can bind to Aβ in plasma.

    Mechanisms of AD induced by Aβ

    There are three hypotheses about the pathogenesis of Alzheimer's disease: beta-amyloid cascade hypothesis, Tau protein hypothesis and vasculogenic hypothesis. Among them, the beta-amyloid cascade hypothesis is dominant. The brain of AD patients deposits senile plaque, whose main component is Aβ. Deposition of Aβ can lead to AD. Decreasing the accumulation of Aβ in the brain can delay or alleviate the symptoms of AD. Aβ is the common pathway of various causes inducing AD, and is the key factor for the formation and development of AD.

    1. Aβ and apoptosis

    Apoptosis is an energy-dependent process of cell suicide caused by activation of intracellular death procedures. It is an autonomous and orderly process of cell death controlled by genes. Normally, apoptosis is a physiological regulation mechanism, which regulates embryonic development, cell differentiation and normal cell renewal in vivo. However, under the interference of pathological factors, apoptotic cells will be abnormal and lead to a variety of diseases. Neuronal loss in cortex and hippocampus is the main pathological feature of AD, and neuronal apoptosis is the main cause of neuronal loss in AD.

    The pathogenesis of AD is closely related to the disorder of brain energy metabolism. As the main place of energy metabolism, mitochondria play an important role in the function of neurons. Mitochondria are not only the target of Aβ damage, but also mediate the toxicity of Aβ to neurons and initiate the apoptotic process of neurons. The toxic effects of Aβ on neurons are mainly manifested in destroying the integrity of cell membrane, disturbing the stability of intracellular environment and inducing central immune inflammatory response. The deposition of Aβ may be an important cause of neuronal degeneration and synaptic loss. Aβ deposition, neuronal death, glial cell infiltration, and the length of damaged dorsal cell zone increase by 4-5 times. Aβ causes neuronal apoptosis through mitochondria.

    1. Aβ and inflammation

    Aβ can activate glial cells, release cytokines and inflammatory mediators, and produce inflammatory response, which indirectly damages nerve cells.  A strong focal inflammatory response exists in the brain of AD patients. Glial cells can produce many inflammatory cytokines, complement proteins and other immune molecules. Neuroglial proliferation was observed in the nucleus, hippocampus and cortex of Meynert, in which microglia were dominant, followed by astrocytes; there were aggregation and phagocytosis of active microglia around blood vessels, shrinkage of neuron cell body, concentration of cytoplasm, consolidation of nuclear chromatin into clumps and marginal aggregation, integrity of nuclear membrane and tendency of apoptosis, decrease of synaptic structure, unclear anterior and posterior membranes, disappearance of synaptic gap, and decrease of synaptic vesicles.The number of synaptic vesicles decreased, the anterior and posterior membranes were not clear, the synaptic gap disappeared, and the number of synaptic vesicles was not significant. The increase of inflammatory proteins and the activation of microglia are closely related to the pathological changes of AD, so immune inflammation may be one of the important factors inducing AD by Aβ. As a stimulant, Aβ accelerates neuronal death by activating peripheral microglia to produce cytokines and immune inflammation in the nervous system. It can also induce memory loss and cognitive impairment, and enhance the activity of Toll-like receptor 2 and 4 agonists, thereby enhancing the immune response. Another new study shows that APP can also activate monocytes and microglia through tyrosine kinase pathway, leading to a large release of inflammatory factors and the production and deposition of Aβ.