Learning the pathology of Alzheimer's Disease.
According to the World Health Organisation 50m of people are currently living with Dementia and it is predicted that in 2050 the number will rise to 152m.
It is characterised by worsting memory loss, deterioration in cognitive abilities and ability to perform daily activities. It is a slowly neuron progressive disease that makes the patient’s health degenerate over time and it usually onsets after 65 years old.
The cause of the symptoms above is the reduction of brain mass occurring because of neurone death. This happens due to tow neuropathological dysfunctions:
1. Extracellular amyloid plaques
APP (amyloid precursor protein) is present in all the cell membrane of each neuron. The APP gene provides instructions for making a protein called amyloid precursor protein. This protein is found in many tissues and organs, including the brain and spinal cord. Little is known about the function of the amyloid precursor protein. In a healthy person, 3 enzymes - Alpha secretes, beta secretes and Gama secretes are responsible for cleaning and destroying the APP protein. These 3 enzymes cut the APP in 3 fragments and send them to proteasomes (a protein degradation complex able to digest numerous proteins in the cell) to be digested.
In the Alzheimer’s disease beta and gamma secretase works way more than the alpha secretase. The problem with this is that the fragments these enzymes break they are not soluble, so the cell is not able to digest them. These fragments start sticking to one another creating aggregations of fragments called Beta Amyloid creating Sinale plaques. These form outside of the cell as they are being pulled OUT of the cell membrane.
Once the Sinale plaques are formed they start activating the immune system which is starting to compensate causing inflammation damaging the brain tissue. Secondly, these beta-amyloid start getting stuck in the synapses interrupting communication between neurons. Thirdly, they start affecting the inside of the cell as explained below.
2. Intracellular neurofibrilattory tangles
Another protein heavily involved in the Alzheimer's disease is the TAU protein. The protein stabilizes the microtubules that run across the axon by keeping molecules together giving it its structure. These microtubules facilitate the transport of neurotransmitters across its length. One of the theories suggests that the beta-amyloid formed outside of the cell hyperphosphorylates the TAU protein causing the cytoskeleton of the microtubules to fall apart. TAU protein starts to aggregate into filaments. Despite extensive studies, the causes leading to abnormal hyperphosphorylation of tau are still not fully understood.
Without the nutrients and neurotransmitters traveling across its axis the cell will die
The disease has very strong genetics links and the ones associated with the disease are:
APP (Chromosome 21 mutation or increased load) as we just discussed
APOE4 (Chromosome 19) - helps the production of gamma secretase
S0RL 1 - associated mainly with late-onset - picks up the APP protein to be moved to compartments where the digestion of the APP results in beta amyloids. A gene still to be studied more in-depth.
What are the symptoms of progressive disease?
Alzhaimer’s start in the Hippocampus - as a result at the beginning patients experience short-term memory as this part of the brain is responsible with embedding new memories. This can be described as Anterograde Amnesia. .
The next part of the brain that gets affected is the area responsible with speech so the patient will start having struggles with talking
As the disease progresses mood imbalances start arising with the patient experiecning mood swings
And finally when the frontal lobe starts get affected the executive functions are destroyed such as personality and decision making.
WHO (2017),Dementia. Available at https://www.who.int/news-room/fact-sheets/detail/dementia [Accessed: 24th of May 2020]
Drbeen Medical Lectures, 2016 Available at: https://www.youtube.com/watch?v=oXKnc3OlTXo [Accessed: 24th of May 2020]
APP Gene, Available at: https://ghr.nlm.nih.gov/gene/APP
Investigating the interactions that cause tau to form tangles in Alzheimer's disease, 2015, Available at: https://www.alzheimers.org.uk/research/our-research/research-projects/investigating-interactions-cause-tau-form-tangles-alzheimers-disease
Gong, C. X., & Iqbal, K. (2008). Hyperphosphorylation of microtubule-associated protein tau: a promising therapeutic target for Alzheimer disease. Current medicinal chemistry, 15(23), 2321–2328. https://doi.org/10.2174/092986708785909111