Alzheimer’s and other conditions that involve misfolded tau protein, known as tauopathies, remain one of the world’s most urgent health challenges. These diseases are marked by the gradual loss of brain cells and memory, and effective treatments are still out of reach. For many years, scientists believed that tau’s role in the brain was relatively simple: to stabilize microtubules, the internal tracks that neurons use to move nutrients, signals, and waste. In disease, excessive chemical modifications called phosphorylation were thought to cause tau to fall off the microtubules, which destabilizes the system and leads to harmful tangles.
New evidence from Dr. McKenney and his colleagues challenges this long-standing view. Their recent discoveries suggest that tau has a much more dynamic role and forms “envelopes” along microtubules that act as gatekeepers to control which proteins and transport motors can access the tracks. In this way, tau envelopes help regulate the balance of activity inside neurons. The team now believes that one of the earliest and most damaging events in Alzheimer’s disease (AD) is the disruption of these envelopes. Their preliminary data strongly supports this new idea. They found that even when tau is phosphorylated at sites known to be altered in AD, it does not simply detach from microtubules. Instead, its tendency to cluster and form envelopes increases, but in ways that destabilize the system. Moreover, they found that abnormal, disease-like tau fibrils still bind to microtubules, where they interfere with normal tau envelopes and block healthy transport. The McKenney lab has also created a living cell system that allows them to watch these processes unfold in real time, providing a powerful new tool for dissecting how normal tau function becomes corrupted. Together, these results point to a unifying explanation: in AD, pathological forms of tau hijack its normal envelope-forming behavior, leading to disrupted transport, cellular stress, and ultimately, neurodegeneration.
To test the validity of their unifying explanation, they have designed two aims. The first aim will determine how disease-associated phosphorylation alters tau’s ability to form and maintain protective envelopes on microtubules. By directly comparing healthy and pathological tau species, they will pinpoint the tipping point at which phosphorylation corrupts tau’s normal role and triggers dysfunction. The second aim will determine if tau envelope disruption is a side effect of Alzheimer’s or a key driver of the disease. They will investigate whether damaged envelopes serve as a launchpad for new aggregates and whether toxic tau from human Alzheimer’s brains can bind to microtubules to destroy healthy envelopes. These experiments will distinguish between whether envelope disruption is a side effect of the disease or a key driver of its progression.
This research has the potential to shift the field’s understanding of tau and open a new path for treatment. By focusing on tau’s physiological role and how it is corrupted early in disease, the team is uncovering a new therapeutic target: stabilizing tau envelopes before irreversible brain damage occurs. If successful, this work could pave the way for first-in-class therapies that prevent or slow AD at its earliest stages, offering hope where current treatments fall short.
