Insights into Alzheimer’s Disease

Like most of the world, the majority of the scientific community has shut down. However, papers and articles that were already in the works are still being published. In fact, just this week a paper was published in the journal Nature examining what happens in the brain during neurodegenerative diseases involving the protein tau. Tau is one of the major proteins that plays a role in the progression of Alzheimer’s Disease (AD). We have two experiments related to AD,(1115 and 1116), so we’re keeping up with the scientific literature and wanted to share this exciting research with you.

Two of the major proteins that play a role in Alzheimer’s Disease are AB plaques and Tau tangles

 Tau is a microtubule protein. Microtubules are the “railroad tracks” of a cell, moving proteins and nutrients back and forth from different areas in the cell. Microtubule function is critical in neurons as they are very long cells requiring sophisticated mechanisms to transport proteins. Tau functions by binding to microtubules to stabilize them in the axon. Normally, tau is not found outside of the axon. However, during AD, tau is mislocalized to both the cell body and the dendrites. This mis-localized tau is also misfolded. Normally a protein has a set secondary and tertiary structure, meaning that it folds in a very precise way. Misfolded tau results in insoluble protein clumps which ultimately contribute to neuronal death.

Lobes of the brain. In Alzheimer’s Disease, misfolded tau is initially detected in the entorhinal cortex, then spreads through the brain.

During the course of AD, misfolded tau spreads throughout the brain. Early on, misfolded proteins can be found in a brain region known as the entorhinal cortex. The entorhinal cortex connects two very important areas of the brain: the hippocampus where memories are formed, and the frontal lobe where executive decisions are made. As the disease progresses, the misfolded tau spreads through the brain, resulting in widespread neuronal death. 

How can one misfolded protein spread from neuron to neuron and result in widespread cell death? It is thought that extracellular misfolded tau can somehow enter a healthy neuron and cause properly folded tau to misfold. However, a protein can’t simply enter any cell it wants. Eukaryotic cell membranes are characterized by a phospholipid bilayer, protecting the intracellular contents. In order for a large protein to enter the cell, it would need to bind to another protein on the cell surface, known as a receptor. The receptor would then facilitate the entry of the extracellular protein. Until this week however, it wasn’t clear what receptor that would be. 

Figure 1 | A surface receptor for tau uptake. Misfolded forms of the protein tau can spread through neurons. a. Normal neuron, b. Neuron without LRP1. Rauch and colleagues1 

In an article published on April 1st, Rauche et al. identify a protein on the surface of a neuron that could serve as the receptor for tau: low-density lipoprotein receptor 1 (LRP1). The team was able to show that isolated neurons without LRP1 on their surface did not internalize as much tau as neurons with LRP1. Additionally, while misfolded tau spreads rapidly through the brain of a normal mouse, if a mouse has less LRP1 on its neurons then the misfolded tau doesn’t spread as quickly. 

This is all very exciting news for Alzheimer’s Disease researchers, however all studies come with some limitations. LRP1 is a critical protein in the brain for excitatory neurotransmission, motor functions, and more. Therefore, targeting LRP1 specifically could lead to even more detrimental outcomes. However, understanding the basic biology behind how tau could spread throughout the brain can open many other doors. Researchers have a wealth of knowledge about the processes in the cell that LRP1 affects and can continue the research by looking at these pathways. By discovering how misfolded tau could spread through the brain, researchers have taken a giant leap in their understanding of Alzheimer’s Disease. 

If you’d like to learn more about neuroscience by performing engaging experiments in your classroom, visit our website: edvotek.com/neurobiology

[1] Rauch, J. N. et al. Nature https://doi.org/10.1038/s41586-020-2156-5 (2020).

[2] Deinhardt K. Nature https://doi.org/10.1038/d41586-020-00874-z (2020).