Author: Suleiman Obeidat Yr 12
The Alzheimer’s Society reports that around 850,000 people in the UK suffer from dementia, a condition characterised by memory loss and cognitive impairment which restricts the patient’s ability to carry out normal everyday tasks. Dementia costs the NHS £34.7 billion for care and is one of the leading causes of death in the country. Alzheimer’s is a neurodegenerative disease which accounts for up to 75% cases of diagnosed dementia. The early detection of Alzheimer’s has been difficult in the past as the pathology of the disease is poorly understood; however, researchers from the University of Cambridge have recently developed special antibodies which can help detect the malformed protein clusters which cause neurological damage in Alzheimer’s. This discovery can greatly aid in the detection of the disease, meaning earlier diagnosis and better understanding of how it develops.
Before discussing the benefit of these antibodies, it is important to first look at our current understanding of how the disease develops and progresses. The neurons in the brain contain an integral protein embedded in their plasma membrane known as Amyloid Precursor Protein or APP. The function of APP remains unknown, but it gets its name due to being a site where amyloids may occur. Amyloid refers to a protein that is misshaped into beta pleated sheets (β-sheet). Normally, the APP gets used, broken down then recycled like any other protein. Enzymes called alpha secretase (α-secretase) and gamma secretase (γ-secretase) cleave or cut the protein at specific points into smaller peptides that are soluble, and the protein is recycled. In Alzheimer’s, another enzyme called beta secretase (β-secretase) cleaves the APP instead of the α-secretase leading to a left-over peptide, known as amyloid beta (Aβ) that isn’t soluble. Aβs are characteristically sticky and so they tend to stick to each other outside of the neuron forming clusters called beta amyloid oligomers which then further develop into beta amyloid plaques. These plaques can then get in between neurons and disrupt the transmission of signals across synapses, which can impair brain function such as memory. Another protein linked with the pathology of Alzheimer’s is the tau protein (τ-protein). These proteins stabilize microtubules inside neurons which act as a skeleton of the cell aiding in the transmission of impulses along the neuron. What happens in Alzheimer’s is that the amyloid beta plaques stimulate the action of an enzyme called kinase in the neuron which transfers phosphate groups to the tau proteins, causing conformational changes which releases them from the microtubules. The tau proteins then clump up with each other forming neurofibrillary tangles which restricts the transmission of impulses along the neuron; this can lead to apoptosis or programmed cell death. Over time, changes in the structure of the brain occur such as atrophy, where the brain shrinks and loses its structure. Clinically, this causes loss of memory and the impairment of many cognitive processes such as problem solving, thinking, decision making and much more.
Recently, research lead by Dr Michele Vendruscolo of the University of Cambridge led to the design of specific antibodies that target certain epitopes on regions on the beta amyloid oligomers. Their method consisted of two phases. The “scanning” phase involves designing a range of antibodies that bind to different epitopes on a target protein, in this case, the amyloid beta protein. This allowed the researchers to identify epitopes that are exposed specifically in the oligomers and not in the other forms of the Aβ protein. The following “mining” phase involves designing the antibody that can only bind to the specific oligomer epitopes identified in the previous phase. This method allowed them to identify and quantify oligomers in both in vitro and in vivo experiments that involved roundworms and hippocampal tissue from mice. Dr Vendruscolo said that the development of this antibody is “an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.” The researchers hope that this will aid in the development of new potential drugs and in earlier diagnosis, as well as provide opportunities for more effective clinical trials with Alzheimer’s patients. For example, a diagnosis can be made if the antibodies indicate abnormal numbers of oligomers or they may be used to identify whether a certain drug is lowering the number of oligomers in brain tissue. The findings of the study were published in the Proceedings of the National Academy of Sciences (PNAS) on June 3rd.
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