Columbia researchers may have uncovered one of the clearest explanations yet for how Alzheimer’s disease-associated tau pathology begins. In two new studies published in Nature Neuroscience, the investigators identified a neuron-specific protein-disposal system that appears to play a critical role in preventing the formation of pathological tau in the brain, offering new insights into the disease and identifying a potential target for future therapies.
The newly identified pathway, known as the neuroproteasome, acts as a unique quality-control system within a neuron’s dendrites to remove newly synthesized proteins before they can accumulate or become dysfunctional. When researchers disrupted the pathway in primary neurons and mouse models expressing humanized tau, tau rapidly formed filaments that closely resembled those found in human Alzheimer’s disease.
The researchers also found that APOE4 and aging, both risk factors for Alzheimer’s disease, appear to impair neuroproteasome function, creating the conditions that favor tau aggregation.
“Formation of these tau aggregates is a major driver of neurodegeneration,” says Kapil Ramachandran, Ph.D., assistant professor of neurological sciences at Columbia and the senior author of the study. “A lot of the focus in the field has been on how to clear these aggregates, but that doesn’t address the problem that they are continually forming. The therapeutic goal for our research is to understand if the process by which these aggregates develop can be targeted, and if we can prevent them from being formed in the first place.”
Discovering the Neuronal Disposal System
The discovery that tau aggregation can originate in dendrites — versus the commonly held belief that it is caused by tau redistribution from axons — and that it is associated with neuroproteasome dysfunction were unexpected findings. Dr. Ramachandran and his team had been studying how neurons maintain protein quality over time, focusing on the adaptations that allow them to withstand cellular stress.
“We figured out that there’s a disposal system that only neurons have that other cells don’t. And we’ve been focusing on how that disposal system works, what it does, and what it gets rid of,” he says. “That’s what led us very serendipitously to this work on Alzheimer’s disease.”
While researchers have long suspected that tau synthesis might play a role in Alzheimer's disease, prior studies lacked the tools needed to precisely track where tau was being produced within neurons. Dr. Ramachandran says STARFISH (spatially resolved translation of endogenous RNA FISH), a high-resolution imaging technique developed in his lab, provided that missing capability, allowing the team to directly observe the process.
A 3D reconstruction captured through STARFISH shows tau proteins (pink) within neuronal dendrites (white). Image from Nature Neuroscience.
With the help of STARFISH, the researchers ran a set of experiments to understand where tau was being made and discovered it was only made in neuronal dendrites; many of these sites were adjacent to neuroproteasomes. When they inhibited neuroproteasome function, they triggered the misfolding of the tau proteins, which triggered tau aggregation. When they stopped protein synthesis, tau no longer aggregated.
“We were just blown away. That’s not what we would have ever anticipated. It’s certainly not how the field has thought about that problem for a long time,” says Dr. Ramachandran. The findings suggest that neuroproteasome may play a critical role in preventing the earliest stages of Alzheimer’s-related tau pathology.
“As we understand more of the basic science about how this complex process works, we can eventually boost its capacity to get rid of [pathological tau] so that we delay when aggregation in Alzheimer’s disease begins,” he adds.
The Roles of APOE4 and Aging in Tau Aggregation
Their studies also identified a link between the presence of APOE4, the strongest genetic risk factor for Alzheimer’s disease, and the risk of developing tau aggregates. Specifically, they found that neuroproteasome abundance at the neuronal plasma membrane declines with age and is differently affected by the three major APOE isoforms: E2, E3, and E4.
Through a series of experiments, the team found that APOE4 impaired neuroproteasome functioning, making neurons more vulnerable to tau aggregation; it reduced the abundance of the protein-disposal complexes by roughly 50%. By contrast, APOE2 had a protective effect on the neuroproteasome, which reduced the likelihood of tau aggregate formation.
The findings show that both genetic risk and aging may impair the same cellular quality-control mechanism, increasing the likelihood that pathological tau aggregates will form.
“I would go as far as to say it’s one of the first links that directly bridges APOE genotype or aging directly to tau aggregation in a linear way,” Dr. Ramachandran says.
Tau Clearing Versus Tau Generation
Much of the recent Alzheimer’s drug developments targeting tau have centered on monoclonal antibodies to clear existing tau aggregates. While these approaches may be effective at removing pathological tau, Dr. Ramachandran is interested in a different approach: identifying opportunities to intervene earlier in the process.
Our research showed one of the first links that directly bridges APOE genotype or aging directly to tau aggregation in a linear way.
— Dr. Kapil Ramachandran
The research provides additional rationale for investigating antisense oligonucleotide (ASO) therapies, which reduce tau development by preventing tau synthesis and may help prevent the earliest stages of pathological tau aggregation. However, important questions remain: “If you get rid of tau entirely, is that good or not? It’s not particularly clear,” Dr. Ramachandran says. “If we can really understand what’s happening through these mechanisms, we could come up with a more specific strategy to prevent tau misfolding without touching the tau that’s supposed to be made in the first place.”
Because tau serves important biological functions in healthy neurons, researchers still need to determine how much reduction can be achieved safely and whether future therapies should target tau production, tau clearance, or both. Dr. Ramachandran believes the answer may lie in better understanding how neurons distinguish normal tau from the subset of newly synthesized tau that appears vulnerable to aggregation.
“Of all the tau that’s made, just 30% to 40% undergoes some type of quality control, whereas the rest is untouched. What differentiates those two populations? I think if we can understand that problem, then we can leverage that for therapeutic benefit.”
