European researchers from the University Medical Center Hamburg-Eppendorf (UKE) and the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) at the University of Cologne have identified a key cellular process that helps explain why dementia risk rises with age.
In experiments using both genetically engineered nematode worms and mouse models, the team found that age-related dementia is closely linked to a declining ability of neurons to remove unwanted, aggregated proteins. As the efficiency of neuronal protein disposal diminishes over time, misfolded and aggregated proteins progressively accumulate in nerve cells. This accumulation is a driving factor in the onset and progression of dementia, according to the study published in the journal Genetics.
“By tracing disease progression in experimental models of dementia and focusing on how neurons eliminate unwanted proteins, we show how these disposal mechanisms are interconnected and how their effectiveness wanes with age,” said Markus Glatzel, M.D., from the Institute of Neuropathology at UKE. “These insights bring us closer to understanding why dementias mainly affect older individuals and to the longer-term goal of developing therapies that restore protein clearance capacity in aging neurons.”
The research team combined genetic and experimental approaches across species to strengthen their conclusions. In Caenorhabditis elegans worms, researchers led by Thorsten Hoppe, Ph.D., at the CECAD Cluster of Excellence selectively inactivated specific protein disposal routes to observe how neurons compensate and which pathways are essential to prevent toxic buildup. These manipulations revealed how different clearance systems interact and which failings most strongly contribute to pathological protein accumulation.
Following the worm experiments, the investigators examined the same cellular pathways in young and aged mice carrying genetic changes that promote neuronal protein aggregation. Comparing the results across species and age groups allowed the scientists to demonstrate a consistent decline in neuronal protein disposal with aging and to link this decline to the development of dementia-like pathology. Together, the cross-species findings provide a mechanistic explanation for the steep increase in dementia incidence with advancing age.
Beyond advancing fundamental understanding, the study highlights neuron protein disposal mechanisms as promising therapeutic targets. Restoring or bolstering the cells’ capacity to clear misfolded proteins could slow, halt, or potentially reverse aspects of neurodegeneration associated with age-related dementias. As Mark Johnston, Ph.D., Editor-in-Chief of Genetics, noted, “This research opens the door to identifying compounds or interventions that might prevent, stop, or reverse the cellular dysfunction underlying dementia.”
The authors emphasize that translating these findings into human treatments will require further work to identify safe and effective ways to improve protein clearance in aging human neurons. Nonetheless, the study provides a clear rationale for drug discovery efforts aimed at enhancing the natural proteostasis systems that preserve neuronal health over a lifetime.
Notes about this dementia research
This work received financial support from multiple funding sources, including the Deutsche Forschungsgemeinschaft (notably FOR885 to M.G. and T.H., the Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) to T.H., and GRK1459 to M.G.), the Medical Research Council (UK) to D.L., the Hans und Ilse Breuer Foundation to S.L., the Leibniz Center Infection Graduate School (Model Systems for Infectious Diseases), and the Landesexzellenzinitiative of Hamburg (SDI-LEXI) to M.G.
Contact: Press Office – Genetics Society of America
Source: Genetics Society of America press release
Image Source: The image is in the public domain.
Original Research: Abstract for “A Novel Interaction Between Aging and ER Overload in a Protein Conformational Dementia” by Angela Schipanski, Sascha Lange, Alexandra Segref, Aljona Gutschmidt, David A. Lomas, Elena Miranda, Michaela Schweizer, Thorsten Hoppe and Markus Glatzel in Genetics. Published online March 1, 2013, doi:10.1534/genetics.112.149088