Beta amyloid (AB) or beta amyloid peptide (ABP) is the name given to peptides of 39-43 amino acids and between 4-6 kDa in molecular weight that are the product of the metabolism of the amyloid precursor protein (APP) when processed by the amyloidogenic route.
The term amyloid (starch-like) refers to the fact that the deposits of this protein resemble the starch granules first seen in reserve plant tissues. Currently, the term is associated with peptides and proteins that adopt a particular fiber morphology in the nervous system .
ABP corresponds to the transmembrane C-terminal segment of the APP protein. The gene encoding APP is located on chromosome 21 and undergoes alternative splicing resulting in various isoforms of the protein.
The different variants or isoforms are expressed throughout the body. The predominant brain isoform is one that lacks the serine protease inhibitory domain.
Small amounts of ABP play an important role in neuronal development and in the regulation of cholinergic transmission, which is essential in the central nervous system . Its abundance depends on a balance between its synthesis and degradation, which is controlled enzymatically.
An important part of the pathophysiological markers of congenital and late Alzheimer’s disease are related to ABP, especially with the formation of senile plaques due to their excessive deposition in neuronal cells, the formation of fibrillar tangles or tangles and synaptic degeneration.
ABP originates from the enzymatic cleavage of the APP precursor protein, which is expressed at high levels in the brain and is rapidly metabolized in a complex manner.
This protein belongs to the family of type 1 transmembrane glycoproteins and its function appears to be to act as a vesicular receptor for the motor protein Kinesin I. It is also involved in the regulation of synapses , neuronal transport and cellular export of iron ions.
The APP protein is synthesized in the endoplasmic reticulum , it is glycosylated and sent to the Golgi complex for its subsequent packaging in transport vesicles that deliver it to the plasma membrane .
It has a single transmembrane domain, a long N-terminal end, and a small intracellular C-terminal portion. It is processed enzymatically in two different ways: the non-amyloidogenic route and the amyloidogenic route.
In the non-amyloidogenic pathway, the APP protein is cleaved by membrane α- and γ-secretases, which cut a soluble segment and the transmembrane fragment, releasing the C-terminal portion that is probably degraded in lysosomes . It is said to be non-amyloidogenic since neither section gives rise to the full ABP peptide.
The amyloidogenic pathway, in contrast, also involves the sequential action of BACE1 β-secretase and the γ-secretase complex, which are also integral membrane proteins.
The α-secretase-induced cleavage releases a protein fragment known as sAPPα from the cell surface, leaving a less than 100 amino acid segment of the C-terminus inserted into the membrane.
This membrane portion is cut by β-secretase, the product of which can be processed multiple times by the γ-secretase complex, giving rise to fragments of different lengths (from 43 to 51 amino acids).
The different peptides fulfill different functions: some can be translocated to the nucleus, exerting a role of genetic regulation; others seem to be involved in the transport of cholesterol through the membrane, while others participate in the formation of plaques or clumps, toxic to neuronal activity.
The primary amino acid sequence of peptide AB was discovered in 1984 by studying the components of amyloid plaques from patients with Alzheimer’s disease.
Since the γ-secretase complex can make promiscuous cuts in the segments released by β-secretase, there are a variety of ABP molecules. Since their structure cannot be crystallized by common methods, they are thought to belong to the class of intrinsically unstructured proteins.
Models derived from studies using nuclear magnetic resonance (NMR) have established that many of the AB peptides have a secondary structure in the form of an α-helix that can evolve into more compact forms depending on the environment where it is found.
Since about 25% of the surface of these molecules has a strong hydrophobic character, it is common to observe semi-stable coils that lead to β-folded conformations, which play a fundamental role in the aggregation states of such peptides.
The neurotoxic effects of these proteins are associated with both soluble forms and insoluble aggregates. Oligomerization occurs intracellularly and larger conglomerates are the most important elements in the formation of senile plaques and neurofibrillary tangles, important markers of neuropathologies such as Alzheimer’s disease.
Mutations in the genes of APP, as well as in the genes encoding the secretases involved in its processing, can cause massive depositions of the AB peptide that give rise to different amyloidopathies, including Dutch amyloidopathy.
The participation of ABP in the release of mediators of the inflammatory response and free radicals has been highlighted, which have harmful effects on the central nervous system by triggering cascades of cell death. It also causes neuronal overgrowth, induces oxidative stress and promotes the activation of glial cells .
Some forms of the AB peptide cause nitric acid formation and excessive calcium ion influx into cells by increasing the expression of ryanodine receptors in neurons, eventually leading to cell death.
Its accumulation in the cerebral blood vessels is known as cerebro-amyloid angiopathy and is characterized by causing vasoconstriction and loss of vascular tone.
Thus, in high concentrations, in addition to its neurotoxicity, the accumulation of ABP weakens the blood flow of the brain structure and accelerates neuronal malfunction.
Since the ABP precursor protein is encoded on chromosome 21, patients with Down syndrome (who have a trisomy on this chromosome), if they reach advanced ages, are more likely to suffer from AB peptide-related diseases.
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