|4. The Beta Amyloid||Alzheimer|
Beta amyloid (Aβ) is a protein fragment snipped from a larger protein called amyloid precursor protein (APP). These fragments (peptides) may aggregate to form a small oligomer, or even mix with other molecules to form a larger plaque which is a hallmark of Alzheimer’s disease (AD).
From APP to Beta Amyloid
APP is one of many proteins associated with the cell membrane. As it is being made inside the cell, APP becomes embedded in the membrane, like a toothpick stuck through the skin of an orange.
Three enzymes are involved in the cleavage of APP: α-secretase, β-secretase and γ-secretase. Depending on which enzyme is involved and the segment of APP where the cleaving occurs, APP processing can follow one of two pathways that have very different consequences for the cell.
In the benign pathway, α-secretase cleaves the APP molecule within the portion that has the potential to become beta-amyloid. This eliminates the production of the Aβ peptide and the potential for plaque buildup. The cleavage releases from the neuron a fragment called sAPPα, which has beneficial properties, such as promoting neuronal growth and survival.
In the harmful pathway, β-secretase first cleaves the APP molecule at one end of the Aβ peptide, releasing sAPPβ from the cell. γ-secretase then cuts the remaining APP fragment at the other end of the Aβ peptide. Following the cleavages at each end, the Aβ peptide is released into the space outside the neuron and begins to stick to other Aβ peptides. These small, soluble aggregates of two, three, four, or even up to a dozen Aβ peptides are called oligomers. Specific sizes of oligomers may be responsible for reacting with receptors on neighboring cells and synapses, affecting their ability to function.
It is likely that some oligomers are cleared from the brain. Those that cannot be cleared clump together with more Aβ peptides. As the process continues, oligomers grow larger, becoming entities called protofibrils and fibrils. Eventually, other proteins and cellular material are added, and these increasingly insoluble entities combine to become the well-known plaques that are characteristic of AD.
The γ-secretase lacks sequence specificity. Its cleavage site may shift slightly, depending on the molecular structure of the enzyme and its environment. As a result, the length of Aβ varies between 40 and 42 amino acid residues. It has been found that the longer one is more likely to aggregate than the shorter one. Researchers usually use two Aβ peptides to compare their toxicities: Aβ with 40 residues (denoted by Aβ40 or Aβ1-40) and Aβ with 42 residues (Aβ42 or Aβ1-42). Aβ42 is more toxic than Aβ40.
Between 1990 and 2010, Aβ was thought to be the main cause of neurotoxicity in AD. However, recent findings and the failure of all Aβ-targeting drugs have demonstrated that the Tau protein plays a more important role than Aβ.
[Adapted from: National Institute on Aging, USA.]