Stem cell therapies and Alzheimer’s disease
The root cause of these plaques is still unknown. Beta- amyloid (Aβ) is formed from a large protein called amyloid precursor protein (APP). The enzymes that cleave (cut) APP are alpha-secretase and beta-secretase. If alpha-secretase cleaves APP there is no for mation of Aβ. However, if APP is cleaved by beta-secretase it can be further cleaved by gamma-secretase to form either a 40 amino acid amyloid peptide which is soluble and harmless, or a 42 amino acid peptide which clumps together to form insoluble amyloid plaques. 14 This amyloid beta peptide is more hydrophobic (water-fearing) and therefore tends to aggregate together more readily than the other amyloid beta peptide. This is known as the hydrophobic effect, whereby molecules clump together to minimize the surface area exposed to water in a solution. 15 The most toxic form of Aβ 42 is in the form of soluble oligomers, which are strings of these units combined. Following on from amyloid plaque formation, two processes play a major role in causing the death of neurons in an infected brain. The first of this is an accumulation of neurofibrillary tangles, made up of a protein called tau. Tau is a vital protein of the cytoskeleton (a system of proteins organizing the organelles of the cell and the movement of these organelles) of neurons, essentially stabilizing the skeletal scaffolding of neurons and their microtubules. The microtubules are transport tubes where substances made in the cell body are transported along within neurons. When tau misfolds and collapses on itself, known as hyperphosphorylation, this leads to collapse of the neuron as it disrupts the cell’s cytoskeleton. 16 When tau detaches from microtubules and sticks to other tau molecules, it can form threads that join to form tangles inside neurons. Th ese tangles block the neuron’s transport system, effectively stopping it from communicating. Neurons full of these tangles soon malfunction and die . 17 The second process is the immune and inflammatory response in the brain. Astrocytes and microglia are the types of brain cells involved in this process. Astrocytes are a type of glial cell with many functions, but the one that is important here is its anti-inflammatory response. Astrocytes become more numerous in AD and these cells become activated to produce arachidonic acid which relieves the inflammation from beta-amyloid plaques. However, an excess amount of this acid causes further damage to neurons due to the change of conditions in the environment. 18 Moreover, microglia orbits neurons and protect them from foreign pathogens (microorganisms that cause disease). If a pathogen is detected, the microglia unload a myriad of toxic chemicals to get rid of the foreign substance. 19 In Alzheimer’s, the internal chaos of plaques and tangles cause t he microglia to go into overdrive, attacking neuronal cells to get rid of the tau and the plaques that are being formed at synapses. The situation becomes worse and worse as the disease progresses.
Vascular problems may also arise, such as beta-amyloid accumulating in the brain arteries, which can lead to mini-strokes. This usually occurs in the later stages of the disease, and can break down the blood
14 Best n.d. 15 Ibid. 16 Jebelli 2017a: 77. 17 What happens to the brain in Alzheimer’s Disease? 2017. 18 Best n.d. 19 Jebelli 2017a: 81.
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