Mechanism of Exacerbated Neuron Loss in Alzheimer’s disease with Co-Pathology of TDP-43 (AD-LATE)

Alzheimer’s disease (AD) is often accompanied by additional forms of brain pathology that can worsen neurodegeneration beyond the effects of amyloid and tau. One of the most common is TDP-43 pathology, in which a protein called TDP-43 becomes dysfunctional and accumulates in abnormal clumps inside neurons. TDP-43 normally helps regulate how cells process RNA, including preventing the production of abnormal RNA sequences called cryptic exons. Loss of this function can contribute to neuronal dysfunction and death. TDP-43 pathology is found in approximately 40–60% of people with AD and related dementias and is associated with greater cognitive decline, but it remains unclear how TDP-43 pathology develops in AD or how it interacts with tau to accelerate neurodegeneration. Understanding this relationship could be particularly important for a form of age-related brain disease known as LATE, in which TDP-43 pathology commonly occurs alongside AD pathology.

Dr. Wong’s preliminary data suggests that tau and TDP-43 may contribute to each other’s dysfunction through a damaging feedback loop. Using a mouse model that develops amyloid and tau pathology (Tau4R-AP*), their team found that TDP-43 dysfunction and abnormal TDP-43 aggregates emerge as the mice age, and that these changes occur after the development of tau pathology. When TDP-43 was removed from neurons, tau pathology spread more rapidly throughout the brain, followed by an earlier and more extensive appearance of TDP-43 aggregates. These findings suggest that loss of TDP-43 function can accelerate tau pathology, while the resulting tau pathology may then drive the development of TDP-43 pathology. Importantly, the team also found evidence that tau and TDP-43 can occur together within the same protein filaments in both their mouse models and human AD and AD-LATE brain tissue. These findings raise the possibility that tau pathology directly promotes TDP-43 aggregation and creates a self-reinforcing cycle that contributes to the loss of vulnerable neurons. They hypothesize that TDP-43 dysfunction accelerates tau pathology, which in turn drives TDP-43 aggregation and further dysfunction, creating a feed-forward cycle that exacerbates neuron loss in AD-LATE.

They will investigate this hypothesis using 2 aims. In the first aim, they will determine how tau and TDP-43 pathology develop relative to one another in their Tau4R-AP mouse models. By examining animals at different ages, they will determine whether tau and TDP-43 co-filaments form before TDP-43 loses its normal RNA-regulating function and whether these changes are followed by increased neuronal loss. In the second aim, they will test whether restoring TDP-43 function can interrupt this cycle. They will use a gene therapy approach to deliver a protein that restores TDP-43’s ability to suppress abnormal RNA sequences in mice with amyloid and tau pathology. They will then determine whether restoring TDP-43 function reduces tau/TDP-43 co-filament formation, TDP-43 aggregation, and neuronal loss.

This work could provide a new explanation for why TDP-43 pathology is associated with more severe neurodegeneration in AD and related diseases. If the proposed studies confirm that tau and TDP-43 drive one another through a feed-forward mechanism, disrupting this cycle could represent a new therapeutic strategy for AD-LATE and other diseases in which tau and TDP-43 pathology occur together. The proposed gene therapy studies will also provide an early test of whether restoring TDP-43 function can protect neurons, potentially supporting future approaches that target TDP-43 alone or in combination with therapies directed against tau.