Biology subjects

Klaassen, R.

Publications and source records attributed to Klaassen, R..

4 recordsLinked to original sources

bioRxiv2026

The TREM-receptor family interactome in the human brain

The Triggering Receptors Expressed on Myeloid cells (TREMs) are a family of cell-surface receptors instrumental in the activation of different myeloid cells. TREM2, its most studied member, is genetically linked to Alzheimer disease (AD), and its interactions with BAmyloid; and APOE have placed it at the forefront of microglia dysfunction in the brain. However, the ligands and binding partners of the other TREM members (TREM1, TREML1, TREML2 and TREML4) are less well defined. Here, we used human AD and non-AD brain lysate to profile the interactome of the ligand binding domains of the different TREM receptors. Besides identifying known ligands for TREM1 (PGLYRP1), TREM2 (C1QL3, LGALSL) and TREML1 (Fibrinogens), we identified complement components and the apolipoproteins APOA1 and APOA4 as novel interactors of TREML1, and heparan sulfate modified proteins as binding partners for TREML2. Furthermore, similar to TREM2, all the TREMLs interacted with the apolipoproteins APOE and Clusterin. Using in vitro pulldowns with heparin, we confirmed that specifically TREML2 interacted with heparan sulfates, in a manner unaffected by the AD-linked S144G mutation. Together, our proteomics approach identified novel interactors for TREML1 and TREML2, cementing the role of the different TREM-proteins in lipid trafficking and immunity.

neuroscience↗

bioRxiv2026

Deletion of astrocyte intermediate filaments GFAP and Vimentin enhances protein synthesis and prevents early synaptic and cognitive dysfunction in a mouse model of Alzheimer's disease

In Alzheimers disease (AD) astrocytes become reactive, displaying hypertrophic morphology, increased expression of intermediate filament proteins GFAP and Vimentin and impaired homeostatic support to neurons. However, the contribution of reactive astrocytes to AD progression, particularly the role of cytoskeletal hypertrophy, remains unclear. Here, we investigate whether astrocyte intermediate filaments actively contribute to early AD progression. We show that astrogliosis appears as early as at 3 months in APP/PS1 mice, preceding amyloid-{beta} plaque deposition, and is characterized by a strong upregulation of GFAP and Vimentin. Genetic ablation of GFAP and Vimentin attenuated astrogliosis, as evidenced by the absence of hypertrophy of astrocyte processes and restored expression of glutamine synthetase and other proteins altered in reactive astrocytes in AD. Importantly, GFAP and Vimentin deletion prevented cognitive decline in 4-month old male and female mice, independently of amyloid plaque pathology or microglial reactivity. Mass-spectrometry based proteomics of the dorsal hippocampus revealed a downregulation of synaptic proteins and dysregulation of ribosomal and RNA-binding proteins in APP/PS1 mice, both of which were rescued by GFAP and Vimentin deletion. Using astrocyte-specific CRISPR-Cas9-mediated knockout of GFAP and Vimentin, we further demonstrate translation impairments in AD astrocytes, and that GFAP and Vimentin deletion restores this impaired astrocytic translation. Together, our findings identify intermediate filament proteins GFAP and Vimentin as active regulators of astrocyte protein synthesis, and reveal a previously unrecognized mechanism by which reactive astrocytes contribute to early cognitive dysfunction in AD. This highlights these astrocyte intermediate filaments as promising therapeutic targets to counteract reactive astrocyte-driven cognitive decline in the early stages of Alzheimers disease.

neuroscience↗

bioRxiv2024

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Decreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimers disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpress Sfrp1 in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.

neuroscience↗

bioRxiv2017

Methods in field chronobiology

Chronobiological research has seen a continuous development of novel approaches and techniques to measure rhythmicity at different levels of biological organization from locomotor activity (e.g. migratory restlessness) to physiology (e.g. temperature and hormone rhythms, and relatively recently also in genes, proteins and metabolites). However, the methodological advancements in this field have been mostly and sometimes exclusively used only in indoor laboratory settings. In parallel, there has been an unprecedented and rapid improvement in our ability to track animals and their behaviour in the wild. However, while the spatial analysis of tracking data is widespread, its temporal aspect is largely unexplored. Here, we review the tools that are available or have potential to record rhythms in the wild animals with emphasis on currently overlooked approaches and monitoring systems. We then demonstrate, in three question-driven case studies, how the integration of traditional and newer approaches can help answer novel chronobiological questions in free-living animals. Finally, we highlight unresolved issues in field chronobiology that may benefit from technological development in the future. As most of the studies in the field are descriptive, the future challenge lies in applying the diverse technologies to experimental set-ups in the wild.

animal behavior and cognition↗