Stopping Tau in its Tracks: Investigating the Spread of Tau Protein in the Brain
Post by Anastasia Sares
What's the science?
The protein tau is an important factor in many kinds of dementia, including Alzheimer’s disease. It normally stabilizes the structural scaffolding of a neuron (the microtubules). In dementia, tau proteins can accumulate and form tangles, harming the function of the cell and eventually leading to cell death. From there, misbehaving tau proteins can also spread and replicate in nearby neurons. However, this spread depends on the tau proteins entering new cells. This week in Nature, Rauch, and colleagues demonstrated that a protein called LRP1 is a key regulator that allows tau to be taken up into the cell and that inactivating LRP1 can stop the spread of this protein.
How did they do it?
The authors used multiple steps to show the effects of LRP1 on tau uptake, starting in vitro (with isolated cells in a petri dish) and then moving to in vivo (inside the tissue of a living animal). In vitro, they used CRISPR-Cas9 technology to edit the genes of cells in a dish, and then exposed them to tau to see how their genetic manipulations affected tau uptake.
Next, the team used viral technology to affect the levels of LRP1 in living mice (in vivo). Half of the mice were exposed to a genetically-modified retrovirus containing a gene that interfered with LRP1 throughout the brain. Then, all mice were exposed to a second retrovirus carrying instructions to generate a tau protein in the hippocampus. The authors monitored the spread of the tau protein from its original region.
What did they find?
In vitro, cells that were manipulated not to produce LRP1 did not allow tau in, and further tests manipulating sub-regions of LRP1 showed that two specific regions of this protein were involved in transporting tau into the cell (MLRP4 and MLRP2).
In vivo, the animals that had LRP1 inactivated showed less spread of tau to other regions of the brain. Tau introduced to one side of the hippocampus did not make it to the other side, nor did it spread to the cortex as it did in mice who had normal LRP1 activity. These experiments demonstrate that LRP1 is 1) involved in taking up tau into the neuron and 2) the spread of tau across the brain.
What's the impact?
In addition to regulating the spread of tau, the protein LRP1 is known to affect amyloid accumulation, the second major factor in neurodegenerative disease. Therefore, this study and others strongly point to LRP1 as an important target for gene therapy, medication, or other treatments.
Rauch et al. LRP1 is a master regulator of tau uptake and spread. Nature (2020). Access the original scientific publication here.