Summary: Reducing the expression of the protein TOM1 in mouse models of Alzheimer’s disease increased the pathology, exacerbated cognitive problems, and raised levels of inflammation in the brain. Restoring TOM1 reversed the effects. Findings suggest a new therapeutic target for treating dementia.
Source: UC Irvine
University of California, Irvine biologists blazing new approaches to studying Alzheimer’s have made a major finding on combating inflammation linked to the disease. The School of Biological Sciences researchers’ discovery about the role of a protein called TOM-1 heralds a shift toward examining the molecular underpinnings of Alzheimer’s processes. Their paper has just been published in Proceedings of the National Academy of Sciences.
“Scientists have known for a long time that inflammation is a driver of Alzheimer’s disease, but inflammation is complex and involves many factors,” said School of Biological Sciences Dean Frank M. LaFerla, Ph.D., whose laboratory conducted the research. “That’s why we decided to look at TOM-1.”
The protein helps to regulate a key component of the inflammatory response. “We were interested in TOM-1 because its levels are low in the Alzheimer’s brain and in the brains of Alzheimer’s rodent models,” said Alessandra C. Martini, Ph.D., the paper’s first author and a postdoctoral researcher who worked with Dean LaFerla. “However, its specific role in the disease has largely been unexplored.”
The scientists discovered that reducing the amount of TOM-1 in Alzheimer’s rodent models increased pathology, which included increased inflammation, and exacerbated cognitive problems associated with the disease. Restoring TOM-1 levels reversed those effects.
“You can think of TOM-1 as being like the brakes of a car and the brakes aren’t working for people with Alzheimer’s,” Dean LaFerla said. “This research shows that fixing the brakes at the molecular level could provide an entirely new therapeutic avenue. With millions of people affected by Alzheimers and the numbers growing, we must research a diverse portfolio of approaches so we can one day vanquish this terrible disease.”
Funding: Funding for the research was provided by the Larry L. Hillblom Foundation, Alzheimer’s Association, National Institutes of Health, Brightfocus Foundation, Instituto de Salud Carlos III of Spain co-financed by European Union Grants, and the Australian National Health and Medical Research Council.
Tom Vasich – UC Irvine
The image is in the public domain.
Original Research: Open access
“Amyloid-beta impairs TOM1-mediated IL-1R1 signaling”. Alessandra Cadete Martini, Angela Gomez-Arboledas, Stefania Forner, Carlos J. Rodriguez-Ortiz, Amanda McQuade, Emma Danhash, Jimmy Phan, Dominic Javonillo, Jordan-Vu Ha, Melanie Tram, Laura Trujillo-Estrada, Celia da Cunha, Rahasson R. Ager, Jose C. Davila, Masashi Kitazawa, Mathew Blurton-Jones, Antonia Gutierrez, David Baglietto-Vargas, Rodrigo Medeiros, and Frank M. LaFerla.
Amyloid-beta impairs TOM1-mediated IL-1R1 signaling
Defects in interleukin-1β (IL-1β)–mediated cellular responses contribute to Alzheimer’s disease (AD). To decipher the mechanism associated with its pathogenesis, we investigated the molecular events associated with the termination of IL-1β inflammatory responses by focusing on the role played by the target of Myb1 (TOM1), a negative regulator of the interleukin-1β receptor-1 (IL-1R1). We first show that TOM1 steady-state levels are reduced in human AD hippocampi and in the brain of an AD mouse model versus respective controls. Experimentally reducing TOM1 affected microglia activity, substantially increased amyloid-beta levels, and impaired cognition, whereas enhancing its levels was therapeutic. These data show that reparation of the TOM1-signaling pathway represents a therapeutic target for brain inflammatory disorders such as AD. A better understanding of the age-related changes in the immune system will allow us to craft therapies to limit detrimental aspects of inflammation, with the broader purpose of sharply reducing the number of people afflicted by AD.