Wim Annaert Lab

Research focus

​Our laboratory is focused on understanding the molecular biology of membrane transport in a disease-related context covering Alzheimer’s disease and congenital disorders of glycosylation type II.

Related to Alzheimer’s, APP cleavage by gamma-secretase leads to amyloid beta peptide production, one possible cause of Alzheimer’s symptoms. gamma-secretase is composed of four proteins – presenilin, nicastrin, PEN-2 and APH-1 – which must come together for cleavage activity. Starting from the idea that Alzheimer’s disease might be slowed by inhibiting g-secretase, we have now identified an endogenous inhibitor that prevents gamma-secretase complex assembly and activity and thus might be targeted for therapy (Spasic et al., 2007). Although all four components are present in the ER, their assembly into functional gamma-secretase is somehow restricted. Assembly begins with the binding of nicastrin to APH-1. This binding is competed early in the secretion pathway by Rer1p, a membrane receptor that retrieves proteins from the Golgi back to the ER. Rer1p binds to nicastrin, thus interfering with nicastrin’s ability to bind APH-1. Decreasing the amount of Rer1p led to an increase in gamma-secretase activity. Exactly what triggers Rer1p to release nicastrin and allow it to bind to APH-1, and subsequently to the other gamma-secretase components, remains to be determined. Preventing this release might provide a means to reduce gamma-secretase activity and thus amyloid plaque formation.

Sporadic Alzheimer’s disease is also characterized by dysfunctions in the neuronal endo-lysosomal system. In this context, we hypothesize that the differential localization of distinct gamma-secretase complexes and substrates at the cell surface and endosomes is part of the mechanism defining specificity in intramembrane proteolysis. We are currently applying high-resolution confocal microscopy to resolve this microdomain association of APP and gamma-secretase components. In addition, we use superparamagnetic nanoparticles for neuronal endosomal targeting. Magnetic isolation followed by ‘organellar proteomics’ will generate proteome inventories of axonal and dendritic endosomal carriers and identify novel early biomarkers for endosomal dysfunction in Alzheimer’s disease and beyond. In a related line of research, we are screening a 10K small-compound library for their effects on inducing axonal and dendritic outgrowth/arborization using a medium-to-high throughput InCell1000 system.

In CDG-II, we identified mutations in sub-units of the COG complex, which are now being used to study the role of this complex in maintaining Golgi-integrity. In a collaborative effort, we also identified patients with mutations in a sub-unit of the V-ATPase linking pH-dependency to proper glycosylation.

Publications

Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular Abeta PoolSannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar A, De Baets G, De Wever V, Habets R, Baert V, Vermeire W, Michiels C, Groot A, Wouters R, Dillen K, Vints K, Baatsen P, Munck S, Derua R, Waelkens E, Basi G, Mercken M, Vooijs M, Bollen M, Schymkowitz J, Rousseau F, Bonifacino J, Van Niel G, De Strooper B, Annaert WCELL, 166, 193-208, 2016
Rer1p maintains ciliary length and signaling by regulating gamma-secretase activity and Foxj1a levelsJurisch N* Rose A* Lu H Raemaekers T Munck S Baatsen P Baert V Vermeire W Scales S Verleyen D Vandepoel R Tylzanowski P Yaksi E De Ravel T Yost H Froyen G Arrington C Annaert WJOURNAL OF CELL BIOLOGY, 200, 709-20, 2013* These authors contributed equally
Lysosomal calcium homeostasis defects, not proton pump defects, cause endo-lysosomal dysfunction in PSEN-deficient cellsCoen K, Flannagan R, Baron S, Carraro-Lacroix L, Wang D, Vermeire W, Michiels C, Munck S, Baert V, Sugita S, Wuytack F, Hiesinger P, Grinstein S, Annaert WJOURNAL OF CELL BIOLOGY, 198, 23-35, 2012
ADP ribosylation factor 6 (ARF6) controls amyloid precursor protein (APP) processing by mediating the endosomal sorting of BACE1Sannerud R, Declerck I, Peric A, Raemaekers T, Menendez G, Zhou L, Veerle B, Coen K, Munck S, De Strooper B, Schiavo G, Annaert WPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 108, E559-68, 2011
A novel strategy for the comprehensive analysis of the biomolecular composition of isolated plasma membranesThimiri D, Ghesquière B, Tharkeshwar A, Coen K, Derua R, Vanderschaeghe D, Rysman E, Bagadi M, Baatsen P, De Strooper B, Waelkens E, Borghs G, Callewaert N, Swinnen J, Gevaert K, Annaert WMolecular Systems Biology, 7, 541, 2011

Job openings

News

VIB scientists announce unexpected breakthrough in Alzheimer’s disease research

15/06/2016 - A research team led by professor Wim Annaert (VIB/KU Leuven) has presented new insights into the roles of different γ-secretases in the development of Alzheimer’s disease (AD).

Analyzing the biomolecular composition of the plasma membrane

15/12/2011 - Wim Annaert, VIB Department of Developmental and Molecular Genetics, K.U. Leuven, developed a new strategy for the comprehensive analysis of the biomolecular composition of only the plasma membrane.

Road block as a new strategy for the treatment of Alzheimer's Disease

22/08/2011 - Two main agents involved in the inception of Alzheimer's disease (APP and beta secretase) follow a different path through the brain cells to meet up, write Wim Annaert and colleagues of VIB and K.U. Leuven in PNAS.

New genetic marker makes fruit fly a better model for the study of neuronal development and human brain disorders

12/11/2010 - VIB researchers attached to the K.U.Leuven have improved the fruit fly as a model for studying the connections between brain cells.

Wim Annaert

Wim Annaert

Research area(s)

Bio

​​PhD: Univ. of Antwerp, Antwerp, Belgium, 1993
Postdoc: Yale Univ., Connecticut, USA, 1994-96
VIB Group leader since 2001

Contact Info

VIB-KU Leuven Center for Brain & Disease ResearchO&N 4, 6e verdCampus GasthuisbergHerestraat 49, bus 602 3000 LEUVENRoute description