Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Robert van der Linden (Donders series 541)

5 April 2022

Promotors: Prof. dr. B. Franke, Prof. dr. M.G.M. Olde Rikkert
Co-promotors: Dr. G.J.V. Poelmans, Dr. T.L. Young-Pearse

Synaptic loss in Alzheimer’s disease: From genes to mechanisms

Synaptic dysfunction is an early event in AD that is closely related to synaptic and neuronal loss and the degree of dementia. The research described in this thesis aimed at increasing our understanding of the AD risk factors that affect synaptic function and eventually loss. We found that somatic mutations that have been shown to accumulate in neurons with aging, the greatest risk factor for AD, have a negative effect on synaptic function as they are more likely to affect longer genes that encode proteins enriched for synaptic functions. We also used a polygenic risk score (PRS)-based approach to elucidate the molecular mechanisms that may be affected by genetic risk factors for AD and found overlap between AD and genetic factors associated with the levels of certain lipids and immune markers in the blood that (again) are linked to synaptic function. Lastly, we showed that higher levels of ELAVL4, an RNA binding protein that has been implicated in AD etiology through multiple lines of evidence, ameliorate AD phenotypes in induced pluripotent stem cell (iPSC)-derived neurons. In light of the thesis findings and while impaired synaptic function in AD can have different underlying causes, therapeutic strategies aimed at increasing synaptic health in general may be beneficial.