**provided by Meredith E. Jackrel from Washington University in St. Louis through a discussion
Abstract:
Alzheimer’s disease is one of the most well-known causations of dementia in the world (“What is Alzheimer's?” n.d.). Consisting in 60-80% of all dementia cases, it causes serious cognitive deterioration, impairing brain functions such as memory and behavior (“What is Alzheimer’s?” n.d.). Studies show that loss or damage of neurons assist in Alzheimer’s detrimental effects, attributed to the presence of highly-stable soluble substances such as amyloid plaques and neurofibrillary tangles (Osmosis 2016). Both plaques and tangles cause clumps inside and outside of neurons, disturbing regular neuron behavior. Research has shown multiple possibilities in ridding of the clumps; one example is the use of dissagregase Heat Shock Protein 104 (Hsp 104), able to reform clumps back into their natural state. As amount of plaques and tangles develop over time, Alzheimer’s is a dangerous and progressive disease that limits one’s ability to live a comfortable life, therefore showing urgency for more extensive research in possible solutions such as Hsp104.
Formation and Consequences of Amyloid Plaques
A protein named amyloid precursor protein (APP), embedded in the cell membrane of a brain neuron, is used to develop and fix neurons (Osmosis 2016). Usually, proteins break apart to become recycled; in APP, enzymes called alpha secretase (α secretase) and gamma secretase (γ secretase) split the precursor protein into soluble fragments. This typical functional route is called the non-amyloidogenic pathway.
However, there are alternative pathways called amyloidogenic pathways (Eisenburg et al. 2012). In this process, instead of α secretase, beta secretase (β secretase) and γ secretase cut up the precursor protein into an insoluble fragment called amyloid beta (Aβ) (Cole et al. 1991).
These insoluble fragments can form chains together in multiple pathways, and in the process of forming these chains, it introduces a distinctive toxicity level for each pathway.** This becomes scary as we do not know which pathways are toxic, and which are not; modern research are accumulating different situations with different amyloidogenic pathways (look into page 4 “Research into Heat Shock Protein 104” for more information).**
Additional to the toxicity introduced from forming chains, these insoluble amyloid fragments clump up in extracellularenvironments, blocking neuron-to-neuron signaling, and thus causing disrupted neuron behavior (Osmosis 2016).
The clumping can also lead to Amyloid Angiopathy where they clump near blood vessels and cause hemorrhage (Osmosis 2:44).
One of the scariest parts of the amyloidogenic pathway is that it is more favorable than the former. The pathway has a more negative Gibbs free energy (ΔG˚) than the non-amyloidogenic pathway (Cole et al. 1991); the more negative ΔG˚ is, the more likely it is to take the path given the trigger of certain environmental factors, mutations, etc.
Formation and Consequences of Neurofibrillary Tangles
Plaques can also trigger intracellular (in-cell) pathways in neurons that cause tau proteins to clump (Osmosis 2016). These proteins interweave in microtubule structure, which acts as transportation systems and structure foundations to cells. By clumping tau protein together, the structure of the microtubule breaks, once again creating abnormal neuron function due to excessive damage (Osmosis 2016).
Research into Heat Shock Protein 104**
Heat shock protein 104, or Hsp104, is a protein disaggregase (unfolding enzyme) found in yeast cells; it is able to break apart aggregates (misfolded clumps) such as insoluble amyloid plaques, α-synuclein (abundant in Parkinson’s disease), and FUS aggregates (prion-like transcription factor proteins found in both sarcoma and Alzheimer’s disease).**
Hsp104 is promising in providing treatments for neurodegenerative diseases as it is able to destabilize the stable confirmations (folding) in aggregates.
To provide context in implementing role of Hsp104 in yeast into humans, a research by Jeremy Ryan et al. “Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma” experimented in infusing multitudes of combinations of aggregate-prone human genes into yeast.
After confirming that the human genes were expressed in the yeast cells, the experiments showed that specific Hsp104 variants (mutants) were able to prevent FUS and FUS-CHOP (FUS domain fused with the CHOP transcription factor and implicating sarcoma) aggregation and “save” yeast from destruction.
Although some yeast were saved, Hsp104 was unable to save yeast certain recombinants with different human genomes.With the uncertainty of knowing which gene-infused yeast recombinants would be saved and which would not, it shows that an accumulation of research discovery is needed for advancing our understanding in such a dangerous disease.**
Conclusion:
As the brain is a vital organ of the body, Alzheimer’s neuron disruption proves that it is a deadly detrimental disease. Despite having extensive research into Alzheimer’s, scientists are still puzzled over causations as there is no implication that Alzheimer’s affects groups of people partaking in a particular activity. The disease affects a considerable portion of our population, and it is important to show care towards people with Alzheimer’s. Hopefully, future research can show promising results in understanding and treating the disease.
References:
Cole, Sarah L, and Robert Vassar. “The Alzheimer's Disease β-Secretase Enzyme, BACE1.” Molecular Neurodegeneration, BioMed Central, 1 Jan. 1991, molecularneurodegeneration.biomedcentral.com/articles/10.1186/1750-1326-2-22.
Eisenberg, David, and Mathias Jucker. “The Amyloid State of Proteins in Human Diseases.” Cell, U.S. National Library of Medicine, 16 Mar. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3353745/.
Osmosis. “Alzheimer's disease - plaques, tangles, causes, symptoms & pathology.” YouTube, 22 Mar. 2016, https://www.youtube.com/watch?v=v5gdH_Hydes&t=217s.
“What Is Alzheimer's?” Alzheimer's Disease and Dementia, Alzheimer's Association, www.alz.org/alzheimers-dementia/what-is-alzheimers.
Ryan, J., Sprunger, M., Holthaus, K., Shorter, J., & Jackrel, M. (2019, July 19). Engineered protein disaggregases mitigate toxicity of aberrant prion-like fusion proteins underlying sarcoma. Retrieved August 14, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6643043/
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