Neurodegenerative Diseases Part 1: Alzheimer’s
Alzheimer’s is a devastating neurodegenerative disease affecting memory. Let’s explore the pathophysiology.
Alzheimer’s is characterized by degeneration of cholinergic neurons in the hippocampus and cerebral cortex, which release ACh, so there is less ACh in the brain. Death of neurons in these areas of the brain contributes to the memory loss characteristic of this condition. Eventually, postsynaptic neurons degenerate too, as they are no longer stimulated by ACh. Risk factors include genetic and environmental factors. Genetic factors include mutations on chromosomes 1, 14, and 21, which result in increased beta-amyloid production. This protein has a high propensity to form aggregates (in this case, plaques) due to the hydrophobic regions, and aggregates contribute to neuronal death. Beta-amyloid is normally a component of neuron cell membrane proteins, but secretases free these proteins from membranes and facilitate aggregation by this mechanism. Therapeutic approaches include mild AChesterase inhibitors (similar to nerve gas but not lethal) to prevent ACh degradation at the synapse, thereby prolonging ACh’s action to the greatest extent possible. This somewhat alleviates symptoms.
Another factor contributing to Alzheimer’s pathogenesis is the accumulation of abnormal tau protein in astrocytes. Normal tau protein stabilizes microtubules, and is hydrophilic. However, it is still prone to aggregation due to small hydrophobic beta-esque regions. Mutation increases the effect of these hydrophobic regions and facilitates aggregation. Accumulation of tau causes formation of neurofibrillary tangles, which contribute to neuronal death by a mechanism similar to that of beta-amyloid plaques.
Here are some sources to learn more:
Campbell’s Biology 9ed Chapter 49.
Vander’s Human Physiology 14ed Chapter 6.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385935/ - Explains the biochemical basis behind tau protein’s propensity for aggregation despite its hydrophilicity and other counterintuitive properties.
https://www.youtube.com/watch?v=GmXJYOlmKFA - A different tau protein-related experiment. It’s irrelevant to Alzheimer’s but I think it’s cool.
