NEW YORK, NY — Researchers at Columbia University have uncovered new clues about the earliest molecular events that may trigger Alzheimer's disease, shedding light on how toxic tau filaments begin to form in the brain. The findings could help guide future therapies aimed at stopping the disease before significant memory loss and cognitive decline occur.
The study focuses on tau, a protein that normally helps stabilize neurons but can become misshapen and accumulate into tangled filaments in the brains of people with Alzheimer's disease. While amyloid plaques have long been associated with Alzheimer's, growing evidence suggests that tau pathology is more closely linked to the progression of cognitive symptoms.
Although recently approved amyloid-clearing therapies have shown modest benefits, many researchers believe tau-focused approaches may prove more effective in slowing or preventing cognitive decline.
Researchers have long sought to understand how tau misfolds into the filaments that make up the tangles associated with Alzheimer's. But because tau does not misfold in animal models of Alzheimer's disease the way it does in people, researchers have had to extract tangles from patients' brains and inject them into animals.
"These prior studies could not capture how tau misfolds in the first place in Alzheimer's disease but understanding how tau aggregation begins is critical if we want to create therapies that prevent neurodegeneration before it starts," says the new study's senior author, Kapil Ramachandran, assistant professor of neurological sciences at Columbia University.
Previously, Ramachandran had found that neurons in the brain have an extra disposal system straddling the neuron's outer membranes. He also found that the extra disposal system, called the neuroproteasome, only destroys newborn proteins, which are highly vulnerable to misfolding.
"In our new study, we wanted to see what would happen if we blocked the neuroproteasome," Ramachandran says. "We had to build a set of molecular tools to make that happen. And that's when we found the tau filaments."
In the current study, the scientists found that disrupting the neuroproteasome rapidly triggered misfolding of tau into filaments which appear highly similar to those seen in patients with Alzheimer's. They also found that ApoE4, a protein known to double Alzheimer's risk, reduces the number of disposal units, leading to a dramatic increase in susceptibility to developing tau tangles. In contrast, ApoE2, a variant that reduces Alzheimer's risk, has the opposite effect.
The researchers saw the same patterns in human brain tissue: People with two copies of the APOE4 gene had far fewer neuroproteasomes in their brains. Neuroproteasomes also declined with increasing age.
"The links between tau filament formation and APOE variants and aging, Alzheimer's greatest risk factors, suggest we may have found a mechanism to explain how an important aspect of the disease gets started," Ramachandran says. "Our hope now is that our findings will lead to the development of therapies that prevent tau tangles from forming in the first place."
