9/21/2022 0 Comments Forget Me Not!
By Sophie Maedo
Junior, Biochemistry major Mississippi State University
Nature Videos 2017 [YouTube Channel] Inside Alzheimer's Brain
The Tau Protein and Neurofibrillary Tangles The Tau, a microtubule-associated protein, is the primary component of NFTs. The Tau protein function to provide stability to microtubules of mature neurons. Tau contains post-translationally modified phosphate groups in its microtubule assembly domain in healthy neurons. In Alzheimer's, a hyperphosphorylated form of Tau accumulates in neurons, resulting in the breakdown of the neural cytoskeleton. A study shows that Tau's phosphorylation at residues outside the microtubule-binding domain detaches Tau from the microtubules resulting in the formation of aggregates. The tau aggregates then accumulate to create the twisted helical filaments known as NFTs. A New Alzheimer's Mechanism For the past thirty years, scientists have mainly conducted research under the amyloid cascade hypothesis. However, a recent study linked impaired autophagy to Alzheimer's disease and proposed that lysosomal dysfunction leads to the formation of amyloid plaques. During autophagy, a section of a neuron's cell membrane elongates to engulf cytoplasm or specific cellular material that needs to be broken down, resulting in the formation of an autophagosome. The autophagosome fuses with a lysosome to form an autolysosome. The lysosomal membrane has vATPase, a proton pump that helps acidify the lysosome. The acidic environment activates hydrolase, which is an enzyme that catalyzes the breakdown of molecules with the use of water. When vATPase function is compromised, it causes the deacidification of lysosomes leading to neurodegenerative diseases. During the autophagy lysosomal pathway, the autolysosome engulfs APPs, breaking these proteins into smaller Aꞵ peptides. The autolysosome can clear these Aꞵ peptides in a healthy cell. However, in cells plagued by Alzheimer's disease, the autolysosome function is compromised, and the concentration of Aꞵ increases. The study also shows that the autolysosome in cells with Alzheimer's disease experienced deficiencies with vATPase early in the disease progression. This results in poor acidification of lysosomes and elevated levels of Aꞵ. An important distinction was that the lysosomal dysfunction occurred before any accumulation of amyloid plaque formation. The observation suggests that amyloid plaque formation could result from faulty lysosomes. While several therapeutic trials and strategies based on the amyloid hypothesis have failed, the new mechanism may provide direction to develop novel treatments that target the dysfunction in the autophagy lysosomal pathway.
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