Modulating the Levels of Tau-Seed Interactors to Treat Alzheimer’s Disease

Neurofibrillary tangles, composed of abnormal forms of the protein tau, stand out as one of the two major hallmark pathologies in Alzheimer’s disease (AD) brains. In AD, tau pathology accumulates after significant amyloid deposition has already occurred—a process that can evolve over decades in AD patients. Increasing levels of pathological tau are strongly associated with neurodegeneration and its appearance in certain parts of the brain may also herald the onset of clinical symptoms. Tau tangles typically emerge first in the temporal lobe in AD brains. Then, coinciding with the onset of clinical symptoms, tau tangles appear to ‘spread’ to other brain regions in a highly stereotypical pattern. Despite many years of research into tau’s normal functions, and its role in synaptic dysfunction, neuronal death, and cognitive deficits under disease conditions, the mechanisms that govern tau propagation between cells and brain regions are still unclear. A better understanding of these processes—and the specific molecules involved—should lead to novel therapies that stop the spread of toxic tau in its tracks.

The propagation of tau pathology occurs over several steps: (1) specific forms of tau (called ‘seeds’) recruit normal healthy tau to aggregate inside a neuron, (2) tau seeds escape—or are released—from the first neuron, and (3) tau seeds enter other neurons. This cycle of recruiting a cell’s healthy tau to form toxic aggregates can then repeat. Researchers, including those within the Alzheimer’s Disease Tau Consortium, are studying tau at each step, i.e., aggregation, release, and entry, as they each hold potential clues that could be leveraged to stop tau from spreading. One clue comes from the observation that pathological tau appears to move mostly between neurons connected through synapses. Further, tau seeds are enriched in synapses isolated from human AD brain tissue. Building on these results, Dr. Lasagna-Reeves’s research specifically focuses on understanding mechanisms of tau propagation at the synapse. He hypothesizes that proteins that normally reside in the synapse (and which support normal functions like the release of neurotransmitters) interact with tau seeds and enable their release from the neuron.

In recent work, Dr. Lasagna-Reeves and colleagues made several important insights. They discovered that a specific form of tau is responsible for most of the ‘seeding’ activity in tau model mice (PS19). They performed experiments to identify all the proteins that interact with this toxic tau seed, and which could help it propagate between neurons. Their results highlighted several interesting candidates, but the top contender was a synaptic protein called ‘Bassoon’. The team further showed that experimentally lowering Basson in tau model mice was protective—it reduced tau spread and the severity of tau pathology in the brain and rescued cognitive function. This work has been highly regarded by the field; Dr. Lasagna-Reeves received an award from the Alzheimer’s Association for this study in 2023 and was a winner of the 2024 Rainwater Prize for Innovative Early-Career Scientists for his ongoing work on tau’s role in neurodegenerative diseases.

In this proposal, the team is essentially following the approach they used above in mice, but to increase the translational potential of their results, they will turn their efforts to finding proteins that interact with tau seeds isolated from human AD brains. They already completed the initial discovery phase in preliminary work and identified 142 proteins of interest that interact with human AD tau seeds; many of these proteins are in the synapse, but they also found a set linked to mitochondrial function. The goal of this proposal is to determine which of these candidates meaningfully impact tau’s ability to spread and trigger other pathologies, to ultimately identify promising targets for future drug development.

This study has three aims. In the first aim, they are lowering (‘knocking down’) levels of the 142 tau-interacting proteins. They are using two model systems with tau pathology: a fruit fly model and human neurons in culture. Fruit flies (Drosophila melanogaster) are a useful lab model for high-throughput screens; their short lifespans and the many available lab tools make genetic engineering and data collection very efficient. Outcome measures in the flies include eye degeneration (a marker of tau-mediated cell death), tau seeding activity, markers of pathological tau, and behavior in a climbing test. Outcome measures in the human neurons include the same tau seeding assay and markers of neuron health. In the second aim, they are selecting ~15 of the most promising candidates from the screens above and testing for a role in contributing to pathology in a tau mouse model (PS19). They are knocking down each tau-interacting gene candidate (one per mouse cohort) and measuring the effect on pathologies of interest using biochemistry and histological methods in brain sections. In the third aim, they are exploring preliminary data suggesting at least two distinct tau seeds in human AD brains, each with a different set of interacting proteins. They are using genetic tools to knock down two genes at a time, one per tau-seed, in PS19 mice. They predict that targeting two different tau-interacting proteins will provide additional benefits, particularly if the distinct tau seeds trigger different pathologies.

In the first year of funding, Dr. Lasagna-Reeves’ team made tremendous progress across the first two aims of the project. They identified several candidate tau-interacting proteins in their fruit fly models, then validated the most promising candidates in animal models. This validation proved very important, as some candidates behaved differently in mouse models than in flies. Their animal studies further narrowed their list of candidate targets, and the team is now poised to complete aim three of the project in the second year of funding. This will consist of a study to knock down candidate genes associated with two different subtypes of tau seeds. By targeting different subtypes of tau seeds simultaneously, Dr. Lasagna-Reeves hopes to achieve more effective reduction and prevention of tau pathology.