Currently more than 55 million people have dementia worldwide and every year there are nearly 10 million new cases. Dementia is currently the seventh leading cause of death and one of the major causes of disability and dependency among older people globally. Alzheimer disease is the most common form of dementia and may contribute to 60–70% of cases. In age-related neurodegenerative diseases, like Alzheimer’s and Parkinson’s, disease-specific proteins become aggregation prone and form amyloid-like deposits.
In this international study a team of researchers led by the European Research Institute for the Biology of Ageing, University of Groningen in collaboration with the German Mouse Clinic, provide evidence of a single endogenous factor, separate from Aβ and its production pathway, contributing to a structural shift of amyloid pathology in a mammalian system. The results were recently published in Life Science Alliance.
The scientists approached the established APPPS1-21 Alzheimer´s Disease mouse model mimicking the human Aβ-pathology in the mouse brain to investigate whether the removal of SERF2 modifies the aggregation of amyloidogenic proteins in the complex environment of the mammalian brain.
Serf2 was identified in a genetic screen in C. elegans before and showed characteristics of a modifier of aggregation. To investigate SERF2 further, conditional Serf2 knockout mice were generated. Surprisingly, it turned out that full body deletion of Serf2 delayed embryonic development, causing premature birth and perinatal lethality. Instead, brain specific Serf2 knockout mice were viable, and showed no major behavioral or cognitive abnormalities. In the APPPS1-21 mouse model, brain depletion of Serf2 altered the binding of structure-specific amyloid dyes, that were previously used to distinguish amyloid polymorphisms in the human brain. These results suggest that Serf2 depletion changed the structure of amyloid deposits, which was further supported by scanning transmission electron microscopy, but more research will be required to confirm this observation.
The results point to pleiotropic functions of SERF2 in embryonic development of mice and in the mouse brain and support the existence of modifying factors of amyloid deposition in mammalian brain, which offer possibilities for polymorphism-based interventions.
Stroo E, Janssen L, Sin O, Hogewerf W, Koster M, Harkema L, Youssef SA, Beschorner N, Wolters AH, Bakker B, Becker L, Garrett L, Marschall S, Hoelter SM, Wurst W, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Thathiah A, Foijer F, van de Sluis B, van Deursen J, Jucker M, de Bruin A, Nollen EA. Deletion of SERF2 in mice delays embryonic development and alters amyloid deposit structure in the brain. Life Sci Alliance. 2023 May 2;6(7):e202201730. doi: 10.26508/lsa.202201730. PMID: 37130781; PMCID: PMC10155860.