Dementia Research

Our Research
The focus or our research is on pathogenic mechanisms that can offer new entry points for early diagnosis and intervention. This includes, but is not limited to, studies of protein homeostasis and cellular stress (Wiep Scheper), altered lipid metabolism (Rik van der Kant), brain network imbalance (Klaus Linkenkaer-Hansen) and its underlying cell physiological causes (Ronald van Kesteren), and novel target discovery using genetics (Danielle Posthuma) and post-mortem brain proteomics (Guus Smit).

Our collaborators
Clinical translation is a key aspect of our research, and we try to identify opportunities for translation as early as possible in our research. To this end we collaborate extensively with clinicians and clinical researchers at the Amsterdam and Rotterdam (Erasmus) University Medical Centers and the AUMC Alzheimer Center, the Amsterdam Neuroscience Industry Alliance Office, and with several industrial and commercial partners.

Our funders
Alzheimer Nederland
ZonMw (Memorabel, TOP, MKMD)
Health Holland
Joined Programing in Neurodegenerative Diseases
Stichtig Proefdiervrij

Our key publications
Untangling the Origin and Function of Granulovacuolar Degeneration Bodies in Neurodegenerative Proteinopathies
VI Wiersma, JJM Hoozemans, and W Scheper
Acta Neuropathol Commun 8:153 (2020)

Somatic TARDBP Variants as Cause of Semantic Dementia
J Van Rooij, M Mol, S Melhem, P van der Wal, P Arp, F Paron, L Donker Kaat, H Seelaar, NB Bank, SSM Miedema, A Uitterlinden, J van Meurs, RE van Kesteren, S A.B., E Buratti, and JC van Swieten
Brain doi:10.1093/brain/awaa317 (2020)

Amyloid-Beta-Independent Regulators of Tau Pathology in Alzheimer Disease
R van der Kant, LSB Goldstein, and R Ossenkoppele
Nat Rev Neurosci 21:21-35 (2020)

Cholesterol Lowering Drugs Reduce APP Processing to Abeta by Inducing APP Dimerization
VF Langness, R van der Kant, U Das, L Wang, RDS Chaves, and LSB Goldstein
Mol Biol Cell mbcE20050345 (2020)

Hyperexcitable PV Interneurons Render Hippocampal Circuitry Vulnerable to Amyloid Beta
S Hijazi, TS Heistek, R van der Loo, HD Mansvelder, AB Smit, and RE van Kesteren
iScience doi:10.1016/j.isci.2020.101271 (2020)

Granulovacuolar Degeneration Bodies Are Neuron-Selective Lysosomal Structures Induced by Intracellular Tau Pathology
VI Wiersma, AM van Ziel, S Vazquez-Sanchez, A Nolle, E Berenjeno-Correa, A Bonaterra-Pastra, F Clavaguera, M Tolnay, RJP Musters, JRT van Weering, M Verhage, JJM Hoozemans, and W Scheper
Acta Neuropathol 138:943-970 (2019)

Cholesterol Metabolism Is a Druggable Axis That Independently Regulates Tau and Amyloid-Beta in iPSC-Derived Alzheimer’s Disease Neurons
R van der Kant, VF Langness, CM Herrera, DA Williams, LK Fong, Y Leestemaker, E Steenvoorden, KD Rynearson, JF Brouwers, JB Helms, H Ovaa, M Giera, SL Wagner, AG Bang, and LSB Goldstein
Cell Stem Cell 24:363-375 e369 (2019)

Genome-Wide Meta-Analysis Identifies New Loci and Functional Pathways Influencing Alzheimer’s Disease Risk
IE Jansen, JE Savage, K Watanabe, J Bryois, DM Williams, S Steinberg, J Sealock, IK Karlsson, S Hagg, L Athanasiu, N Voyle, P Proitsi, A Witoelar, S Stringer, D Aarsland, IS Almdahl, F Andersen, S Bergh, F Bettella, S Bjornsson, A Braekhus, G Brathen, C de Leeuw, RS Desikan, S Djurovic, L Dumitrescu, T Fladby, TJ Hohman, PV Jonsson, SJ Kiddle, A Rongve, I Saltvedt, SB Sando, G Selbaek, M Shoai, NG Skene, J Snaedal, E Stordal, ID Ulstein, Y Wang, LR White, J Hardy, J Hjerling-Leffler, PF Sullivan, WM van der Flier, R Dobson, LK Davis, H Stefansson, K Stefansson, NL Pedersen, S Ripke, OA Andreassen, and D Posthuma
Nat Genet 51:404-413 (2019)

Early Restoration of Parvalbumin Interneuron Activity Prevents Memory Loss and Network Hyperexcitability in a Mouse Model of Alzheimer’s Disease
S Hijazi, TS Heistek, P Scheltens, U Neumann, DR Shimshek, HD Mansvelder, AB Smit, and RE van Kesteren
Mol Psychiatry doi:10.1038/s41380-019-0483-4 (2019)

Proteomics Analysis Identifies New Markers Associated with Capillary Cerebral Amyloid Angiopathy in Alzheimer’s Disease
DC Hondius, KN Eigenhuis, THJ Morrema, RC van der Schors, P van Nierop, M Bugiani, KW Li, JJM Hoozemans, AB Smit, and AJM Rozemuller
Acta Neuropathol Commun 6:46 (2018)

An EEG Nicotinic Acetylcholine Index to Assess the Efficacy of Pro-Cognitive Compounds
S Simpraga, HD Mansvelder, GJ Groeneveld, S Prins, EP Hart, SS Poil, and K Linkenkaer-Hansen
Clin Neurophysiol 129:2325-2332 (2018)

EEG Machine Learning for Accurate Detection of Cholinergic Intervention and Alzheimer’s Disease
S Simpraga, R Alvarez-Jimenez, HD Mansvelder, JMA van Gerven, GJ Groeneveld, SS Poil, and K Linkenkaer-Hansen
Sci Rep 7:5775 (2017)

Susceptible Genes and Disease Mechanisms Identified in Frontotemporal Dementia and Frontotemporal Dementia with Amyotrophic Lateral Sclerosis by DNA-Methylation and Gwas
E Taskesen, A Mishra, S van der Sluis, R Ferrari, FTDGC International, JH Veldink, MA van Es, AB Smit, D Posthuma, and Y Pijnenburg
Sci Rep 7:8899 (2017)

Profiling the Human Hippocampal Proteome at All Pathologic Stages of Alzheimer’s Disease
DC Hondius, P van Nierop, KW Li, JJ Hoozemans, RC van der Schors, ES van Haastert, SM van der Vies, AJ Rozemuller, and AB Smit
Alzheimers Dement 12:654-668 (2016)

The Unfolded Protein Response in Neurodegenerative Diseases: A Neuropathological Perspective
W Scheper, and JJ Hoozemans
Acta Neuropathol 130:315-331 (2015)

Hippocampal Extracellular Matrix Levels and Stochasticity in Synaptic Protein Expression Increase with Age and Are Associated with Age-Dependent Cognitive Decline
MJ Vegh, A Rausell, M Loos, CM Heldring, W Jurkowski, P van Nierop, I Paliukhovich, KW Li, A del Sol, AB Smit, S Spijker, and RE van Kesteren
Mol. Cell. Proteomics 13:2975-2985 (2014)

PRKAR1B Mutation Associated with a New Neurodegenerative Disorder with Unique Pathology
TH Wong, WZ Chiu, GJ Breedveld, KW Li, AJ Verkerk, D Hondius, RK Hukema, H Seelaar, P Frick, LA Severijnen, GJ Lammers, JH Lebbink, SG van Duinen, W Kamphorst, AJ Rozemuller, B Netherlands Brain, EB Bakker, N International Parkinsonism Genetics, M Neumann, R Willemsen, V Bonifati, AB Smit, and J van Swieten
Brain 137:1361-1373 (2014)

Reducing Hippocampal Extracellular Matrix Reverses Early Memory Deficits in a Mouse Model of Alzheimer’s Disease
MJ Vegh, CM Heldring, W Kamphuis, S Hijazi, AJ Timmerman, KW Li, P van Nierop, HD Mansvelder, EM Hol, AB Smit, and RE van Kesteren
Acta Neuropathol Commun 2:76 (2014)

The Unfolded Protein Response Mediates Reversible Tau Phosphorylation Induced by Metabolic Stress
JM van der Harg, A Nolle, R Zwart, AS Boerema, ES van Haastert, AM Strijkstra, JJ Hoozemans, and W Scheper
Cell Death Dis 5:e1393 (2014)

Integrative Eeg Biomarkers Predict Progression to Alzheimer’s Disease at the MCI Stage
SS Poil, W de Haan, WM van der Flier, HD Mansvelder, P Scheltens, and K Linkenkaer-Hansen
Front Aging Neurosci 5:58 (2013)