In Neuronal Branches, the Alzheimer’s Disease-Associated Protein Tau Is Synthesized and Partly Degraded Immediately

In Neuronal Branches, the Alzheimer’s Disease-Associated Protein Tau Is Synthesized and Partly Degraded Immediately

In a paper published on August 13, researchers used STARFISH, a method that shows where a ribosome is currently reading the instructions for producing a specific protein. In primary mouse neurons, the method detected tau synthesis in dendrites, the branches that receive signals from other cells. There, the neuroproteasome, a membrane-associated protein degradation complex, rapidly broke down about one-third of newly synthesized tau. Blocking this complex caused aggregates to accumulate in neurons and in a mouse model expressing human tau, and their formation depended on new protein synthesis.

In the healthy brain, tau is concentrated mainly in axons, the long processes through which neurons transmit signals to other cells. In Alzheimer’s disease, some tau appears in the cell body and dendrites, where it forms protein deposits. The authors asked whether some of this protein might be produced directly in dendrites.

An mRNA map shows where the cellular instructions for producing a protein are located. STARFISH detects those instructions while a ribosome is reading them and assembling the protein. When drugs removed ribosomes from the instructions or allowed them to finish reading, the STARFISH signal disappeared. In mouse neurons, the tau mRNA map covered the cell body and processes, whereas STARFISH detected active tau synthesis only in dendrites. Three-dimensional reconstruction distinguished these dendrites from crossing axons.

In primary mouse neurons, the authors labeled newly synthesized tau for 30 seconds and tracked its fate. Almost half of the label disappeared within another 30–60 seconds. iBEp, a compound that blocks the neuroproteasome, stopped this rapid degradation. The authors estimated that the neuroproteasome breaks down about one-third of newly synthesized tau.

The authors also tested whether blocking the neuroproteasome causes tau deposits to form. Two chemically distinct compounds that block this complex caused tau to accumulate in cultured neurons expressing human tau. A protein synthesis inhibitor suppressed the formation of these deposits. In the hippocampus of mice expressing human tau, co-injection of iBEp and a protein synthesis inhibitor reduced the amount of insoluble tau, phosphate-tagged tau, and stainable aggregates after 72 hours compared with iBEp alone.

In mouse neurons and a mouse model, tau is synthesized in dendrites, the neuroproteasome breaks down some of the newly synthesized protein, and blocking the neuroproteasome allows recently synthesized tau to accumulate in aggregates.