Dr. F.W. Van Leeuwen
Prof. D.A. Hopkins
Prof. H. Steinbusch
R. Gentier MSc.
Focus of research:
Protein quality control in Alzheimer’s disease
Efficient neuronal function depends on cellular homeostasis. In view of the modest number of human genes, other mechanisms such as posttranslational modifications (e.g., ubiquitination and phosphorylation) must contribute too many functions such as control of short-lived proteins, transcription factors and degradation of aberrant proteins. These homeostatic control mechanisms are often flawed during aging and disease. Our research focuses on quality control mechanisms such as exerted by the ubiquitin-proteasome system (UPS). We have discovered that mutant ubiquitin (UBB+1) accumulates in the hallmarks of Alzheimer’s disease (AD), suggesting that it has a function in this multifactorial disease. Indeed, UBB+1 inhibits the UPS dose dependently and results in neuronal dysfunction. We developed tools (e.g., transgenic animals) to study the effects of UBB+1 in vivo. We have addressed anatomical , neurochemical and behavioural aspects (e.g., nest building, Morris water maze and fear conditioning) in these UBB+1mice (line#3413) as well as genetic crossbreeds with the Alzheimer mouse model line (APP-Swe/PSEN1, ∆ exon9). Significantly, interactions between UBB+1 and Aβ plaque formation have already been shown, e.g., plaque load changes.
Aβ plaque formation is a prominent cellular hallmark of AD. To date, immunization trials in AD patients turned out not to be effective in terms of curing or ameliorating dementia. However, in studies on transgenic animals (line 85; APP Swe PSEN1Δexon 9) it was shown that there is limited clearance of pre-existing amyloid plaques. Most likely, immunization trials in humans were initiated too late, suggesting treatment of AD needs to start earlier which is not yet a realistic option. Therefore, more knowledge on the mechanism of Aβ plaque formation is required before reconsidering trials. Our new data implicate that there is strong cross talk between a failing protein quality control by the UPS and Aβ plaque formation mediated via specifically by γ secretase.
For more than a decade a relation between a dysfunctional UPS and Aβ plaque formation has been surmised. Recently, it was shown that pooled GWAS studies, pathway analysis and proteomics also identified protein ubiquitination as one of the key modulators of AD and pointed to a dysfunctional UPS as a causative factor of AD. It is now possible to address this issue by using our transgenic lines (e.g., lines #3413 with postnatal UBB+1 overexpression and proteasomal inhibition, line#85 with Aβ plaque formation starting at 4 months of age and their crossbreed (i.e., lines #3413 x #85. What we know: In the crossbreed Aβ plaque generation is attenuated during the critical period by a dysfunctional UPS while γ secretase activity (not those of α and β) is enhanced resulting in impaired contextual memory. Apparently there is strong interaction between a failing protein quality control and Aβ plaque formation. What is not known: The mechanism of the link between the UPS and Aβ plaque formation is unknown. We surmise that synoviolin expression is upregulated and RER1 (retention in endoplasmic reticulum) is down regulated in the crossbreed. These results show a striking inverse correlation between γ secretase activities and Aβ plaque load and will contribute to a better understanding of strategies to ameliorate or cure AD, via γ secretase modulation.