AC Immune Extends Work Into TDP-43 Protein’s Role in Alzheimer’s

Yedida Y Bogachkov PhD avatar

by Yedida Y Bogachkov PhD |

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AC Immune has announced it will extend its partnership with researchers at the University of Pennsylvania to further study the mechanisms underlying disease-causing changes in  the transactive response DNA binding protein 43 kDa (TDP-43).

Specifically, company researchers and those with the university’s Center for Neurodegenerative Disease Research at the Perelman School of Medicine are looking into what causes TDP-43 misfolding, aggregation, and cell-to-cell transmission.

Over the last two years, this collaboration has shown that TDP-43 aggregates in the brain have different patterns of spreading and transmission depending on the neurodegenerative disease being studied, whether Alzheimer’s diseaseamyotrophic lateral sclerosis (ALS), or subtypes of frontotemporal lobar degeneration-TDP (FTLD-TDP). This indicates that there are distinct disease-causing species of TDP-43.

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“TDP-43 pathology is strongly associated with cognitive decline and episodic memory loss in neurodegenerative diseases, such as FTLD and ALS, and also plays an important role in Alzheimer’s disease,” Virginia M.Y. Lee, PhD, director of the neurodegenerative research center at the University of Pennsylvania (Penn), said in a press release.

TDP-43 is a protein usually found within the cell nucleus, where it stabilizes RNA — the messenger molecule which carries the instructions contained within a cell’s DNA for protein production.

However, specific mutations can cause TDP-43 to become abnormally shaped and accumulate in the cytoplasm, instead of the nucleus, leading to its accumulation and clumping within nerve cells.

These protein aggregates are able to spread from one cell to another, ultimately leading to the progressive loss of cellular function within nerve cells.

Approximately 50% of Alzheimer’s patients show signs of TDP-43 aggregation, which is thought to contribute to symptom severity.

Continued work aims to further clarify the role that distinct TDP-43 species may have in various neurodegenerative diseases.

By developing new experimental models, AC Immune and Penn researchers hope to determine the underlying mechanism behind cell-to-cell transmission of TDP-43, which could enable the development of new therapies targeting TDP-43-related diseases.

AC Immune currently has an anti-TDP-43 antibody in preclinical (lab) development, which has been shown to significantly reduce the disease-causing form of TDP-43 in the brain and displayed neuroprotective effects in mouse disease models.

The company is also developing a TDP-43 positron emission tomography (PET) tracer, which could help locate and measure the amount of TDP-43 protein aggregates in nerve cells during imaging exams, and to measure responses to treatment.