Alzheimer's-Linked Tau Protein May Form in the Wrong Place From the Start, Study Finds

A protein long thought to play a critical role in Alzheimer's disease may not originate where scientists assumed, according to a study from Columbia University that could point to new ways to intervene in the disease. Alzheimer's is marked by harmful buildups of two proteins: amyloid, a misfolded fragment that clumps into plaques between nerve cells, and tau, which forms sticky knots inside neurons, especially in the branching structures called dendrites. In a healthy cell, tau normally concentrates in the axon — the neuron's long "trunk" — where it helps support the scaffolding that shapes the cell membrane. Scientists have long assumed that abnormal tau detaches from that scaffold in the axon and drifts into the dendrites, where it becomes tangled.

Senior author Kapil Ramachandran, a neurologist at Columbia, and his team developed a new visualization method called STARFISH, which uses tailor-designed probes to pinpoint where a specific messenger RNA (mRNA) is being translated into a protein inside a cell. Unlike existing tools, which modify proteins as they are made and risk altering their distribution, STARFISH tracks the act of translation itself with the precision of individual codons, the three-letter genetic units that specify each amino acid.

Applying the method to neurons taken from mice, the researchers found that although mRNA carrying the instructions for tau was present throughout the cell, it was translated into protein only inside the dendrites, not in the axon. "The field has largely focused on tau moving to the wrong place. Instead, we found that a vulnerable pool of tau is being made in dendrites all along," Ramachandran said. The researchers suspect twisted forms of tau may be produced there from the start, tangling together before they can be transported elsewhere — pointing to a possible breakdown in quality control at the protein's production site, rather than damage occurring afterward, in Alzheimer's brains.

The team's earlier work identified a structure called the neuroproteasome among the cell's translation machinery, which is thought to help weed out misfolded proteins. "If we can understand these pathways and triage systems, we may find new ways to ensure that tau folds properly and prevent it from taking a pathological turn," Ramachandran said. The study was published in Nature Neuroscience.