Editors' ChoiceNeurodegeneration

Blocking tau propagation

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Science Signaling  21 Apr 2020:
Vol. 13, Issue 628, eabc3149
DOI: 10.1126/scisignal.abc3149

Knockdown of the receptor LRP1 in mice reduces the spread of the protein tau between neurons.

Some forms of dementia, including Alzheimer’s disease (AD), are known as tauopathies because of the characteristic deposition and spread of aggregates of the microtubule-associated protein tau in the brain. Misfolded (pathogenic) forms of tau interact with normal forms of the protein in healthy neurons in a prion-like manner, leading to misfolding of the normal protein and the spread of intracellular protein aggregates from one neuron to another (see commentary by Deinhardt). Heparan sulfate proteoglycans (HSPGs) are implicated in tau uptake, and low-density lipoprotein receptors (LDLRs) interact with HSPGs to mediate neuronal uptake of β-amyloid, the main constituent of the amyloid plaques that are also associated with AD. Rauch et al. found that knockdown of the LDLR family member LRP1, but not other family members, blocked the uptake of monomeric tau protein, tau oligomers, and a disease-associated mutant tau protein by H4 neuroglioma cells. Incubation of the cells in medium containing the lipid transporter ApoE (an LRP1 binding partner) reduced the endocytosis of tau. Mutational analysis showed that the tau-LRP1 interaction depended on lysine residues in the microtubule-binding repeat region of tau. Noting that LRP1 is present in neurons at the post-synaptic density, the authors used CRISPR to reduce LRP1 abundance in human induced pluripotent stem cell–derived neurons (iPSNs) and showed a substantial reduction in tau endocytosis. In an adeno-associated virus–based mouse model used to track the spread of human tau protein in the brain, shRNA-mediated knockdown of LRP1 substantially reduced tau propagation compared with that in brains expressing control shRNA. Together, these data indicate that LRP1 mediates the spread of tau in the brain, suggesting this pathway may be a therapeutic target to treat diseases such as AD.

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