Our goal is to understand the specific molecular, cellular and network adaptations that occur in the brain in the earliest stages of Alzheimer’s diseasse, and to test how these adaptations can be used for early disease diagnosis and intervention.
The brain contains many different types of neurons, and brain diseases often originate from a selective vulnerability of neuronal subtypes towards specific pathogenic factors. In Alzheimer’s disease (AD), a selective vulnerability of inhibitory interneurons towards amyloid-beta has been proposed as an early factor in disease pathogenesis and an important contributor to early cognitive decline. In my group we were able to show that one particular type of interneurons, so-called parvalbumin-positive (PV) interneurons, are hyperexcitability at an early disease stage in an APP/PS1 mouse model of AD. Restoring PV cell excitability in APP/PS1 mice at this early disease stage rescued neuronal network balance and memory, whereas introducing PV cell hyperexcitability artificially in wildtype mice enhanced the disruptive effects of amyloid-beta on neuronal network balance and memory. PV cell hyperexcitability can therefore be regarded as both a causal factor and a risk factor in AD.
My research currently focusses on
1. Identification of additional interneuron subtypes whose dysfunction may contribute to early AD pathogenesis;
2. The impact of interneuron hyperexcitability on neuronal networks in vivo, and how to translate these findings to earlier and better diagnosis of AD in humans;
3. The identification of specific channels and receptors that contribute to interneuron hyperexcitability and may be targeted for pharmacological intervention;
4. The specific role of interneuron hyperexcitability in the formation and reactivation memory engrams;
5. The role of interneuron hyperexcitability in mouse models of sporadic AD, such as hAPOE3/4 mice.
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 Comm 2:76 (2014)
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)
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)
We use cultured mouse primary hippocampal and cortical neurons as well as human iPSC-derived neurons combined with high-throughput and high-content microscopy in several research projects and in various national and international academic and commercial collaborations.
For an overview of our facilities see High-Content Screening at CNCR.
For examples of our work involving high-content screening see
High Content Screening in Neurodegenerative Diseases.
S Jain, RE van Kesteren, and P Heutink, J Vis Exp e3452 (2012)
Combined Cellomics and Proteomics Analysis Reveals Shared Neuronal Morphology and Molecular Pathway Phenotypes for Multiple Schizophrenia Risk Genes.
M Rosato, S Stringer, T Gebuis, I Paliukhovich, KW Li, D Posthuma, PF Sullivan, AB Smit, and RE van Kesteren, Mol. Psychiatry doi:10.1038/s41380-019-0436-y (2019)