publications

2024

1. Spatially resolved gene signatures of white matter lesion progression in multiple sclerosis

   Astrid M. Alsema, Marion H. C. Wijering, Anneke Miedema, Janssen M. Kotah, Mirjam Koster, Merel Rijnsburger, Hilmar R. J. Weering, Helga E. Vries, Wia Baron, Susanne M. Kooistra, and Bart J. L. Eggen

   Nat Neurosci, Nov 2024

   *Alsema AM, Wijering MHC, Miedema A, and Kotah JM contributed equally

   Abs DOI

   Multiple sclerosis (MS) is an inflammatory disease of the central nervous system characterized by myelin loss and progressive neurodegeneration. To understand MS lesion initiation and progression, we generate spatial gene expression maps of white matter (WM) and grey matter (GM) MS lesions. In different MS lesion types, we detect domains characterized by a distinct gene signature, including an identifiable rim around active WM lesions. Expression changes in astrocyte-specific, oligodendrocyte-specific and microglia-specific gene sets characterize the active lesion rims. Furthermore, we identify three WM lesion progression trajectories, predicting how normal-appearing WM can develop into WM active or mixed active-inactive lesions. Our data shed light on the dynamic progression of MS lesions.

2. An anti-aging vaccine: BCG turns back the clock on remyelination failure

   Janssen M. Kotah, and Bart J. L. Eggen

   Immunity, Sep 2024

   Abs DOI

   Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.

3. Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

   Janssen M. Kotah, Mandy S. J. Kater, Niek Brosens, Sylvie L. Lesuis, Roberta Tandari, Thomas M. Blok, Luca Marchetto, Ella Yusaf, Frank T. W. Koopmans, August B. Smit, Paul J. Lucassen, Harm J. Krugers, Mark H. G. Verheijen, and Aniko Korosi

   Alzheimers Dement, Mar 2024

   *Kotah JM and Kater MSJ contributed equally

   Abs DOI

   INTRODUCTION: Early-life stress (ES) increases the risk for Alzheimer’s disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear. METHODS: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence. RESULTS: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins. DISCUSSION: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD.

2022

1. Sex-dependence and comorbidities of the early-life adversity induced mental and metabolic disease risks: where are we at?

   Kitty Reemst, Silvie R. Ruigrok, Laura Bleker, Eva Naninck, Tiffany Ernst, Janssen Kotah, Paul J Lucassen, Tessa J Roseboom, Bart JA Pollux, Susanne Rooij, and Aniko Korosi

   Neuroscience & Biobehavioral Reviews, Mar 2022

   Abs DOI

   Sex-dependence and comorbidities of the early-life adversity induced mental and metabolic disease risks: where are we at?, Neuroscience and Biobehavioral Reviews, () doi:https://doi. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2. Early-life stress lastingly impacts microglial transcriptome and function under basal and immune-challenged conditions

   Kitty Reemst, Laura Kracht, Janssen M. Kotah, Reza Rahimian, Astrid A.S. Irsen, Gonzalo Congrains Sotomayor, Laura N. Verboon, Nieske Brouwer, Sophie Simard, Gustavo Turecki, Naguib Mechawar, Susanne M. Kooistra, Bart J.L. Eggen, and Aniko Korosi

   Translational psychiatry, Dec 2022

   *Reemst K, Kracht L, Kotah JM, and Rahimian R contributed equally

   Abs DOI

   Early-life stress (ELS) leads to increased vulnerability to psychiatric disorders including depression later in life. Neuroinflammatory processes have been implicated in ELS-induced negative health outcomes, but how ELS impacts microglia, the main tissue-resident macrophages of the central nervous system, is unknown. Here, we determined the effects of ELS-induced by limited bedding and nesting material during the first week of life (postnatal days [P]2–9) on microglial (i) morphology; (ii) hippocampal gene expression; and (iii) synaptosome phagocytic capacity in male pups (P9) and adult (P200) mice. The hippocampus of ELS-exposed adult mice displayed altered proportions of morphological subtypes of microglia, as well as microglial transcriptomic changes related to the tumor necrosis factor response and protein ubiquitination. ELS exposure leads to distinct gene expression profiles during microglial development from P9 to P200 and in response to an LPS challenge at P200. Functionally, synaptosomes from ELS-exposed mice were phagocytosed less by age-matched microglia. At P200, but not P9, ELS microglia showed reduced synaptosome phagocytic capacity when compared to control microglia. Lastly, we confirmed the ELS-induced increased expression of the phagocytosis-related gene GAS6 that we observed in mice, in the dentate gyrus of individuals with a history of child abuse using in situ hybridization. These findings reveal persistent effects of ELS on microglial function and suggest that altered microglial phagocytic capacity is a key contributor to ELS-induced phenotypes.

2021

1. Early-life stress does not alter spatial memory performance, hippocampal neurogenesis, neuroinflammation, or telomere length in 20-month-old male mice

   Janssen M. Kotah, Lianne Hoeijmakers, Erik Nutma, Paul J. Lucassen, and Aniko Korosi

   Neurobiology of Stress, Nov 2021

   DOI
2. Adult food choices depend on sex and exposure to early-life stress: Underlying brain circuitry, adipose tissue adaptations and metabolic responses

   Silvie R. Ruigrok, Janssen M. Kotah, Jesse E. Kuindersma, Eva Speijer, Astrid A.S. Irsen, Susanne E. Fleur, and Aniko Korosi

   Neurobiology of Stress, Nov 2021

   Abs DOI

   Exposure to early-life stress (ES) increases the risk to develop obesity later in life, and these effects may be sex-specific, but it is currently unknown what underlies the ES-induced metabolic vulnerability. We have previously shown that ES leads to a leaner phenotype under standard chow diet conditions, but to increased fat accumulation when exposed to an unhealthy obesogenic diet. However these diets were fed without a choice. An important, yet under investigated, element contributing to the development of obesity in humans is the choice of the food. There is initial evidence that ES leads to altered food choices but a thorough testing on how ES affects the choice of both the fat and sugar component, and if this is similar in males and females, is currently missing. We hypothesized that ES increases the choice for unhealthy foods, while it at the same time also affects the response to such a diet. In a mouse model for ES, in which mice are exposed to limited nesting and bedding material from postnatal day (P)2–P9, we investigated if ES exposure affected i) food choice with a free choice high-fat high-sugar diet (fcHFHS), ii) the response to such a diet, iii) the brain circuits that regulate food intake and food reward and iv) if such ES effects are sex-specific. We show that there are sex differences in food choice under basal circumstances, and that ES increases fat intake in females when exposed to a mild acute stressor. Moreover, ES impacts the physiologic response to the fcHFHS and the brain circuits regulating food intake in sex-specific manner. Our data highlight sex-specific effects of ES on metabolic functioning and food choice.

2020

1. Characterization of astrocytes throughout life in wildtype and APP/PS1 mice after early-life stress exposure

   Maralinde R. Abbink, Janssen M. Kotah, Lianne Hoeijmakers, Aline Mak, Genevieve Yvon-Durocher, Bram Van Der Gaag, Paul J. Lucassen, and Aniko Korosi

   Journal of Neuroinflammation, Mar 2020

   *Abbink MR & Kotah JM contributed equally

   Abs DOI

   Background: Early-life stress (ES) is an emerging risk factor for later life development of Alzheimer’s disease (AD). We have previously shown that ES modulates amyloid-beta pathology and the microglial response to it in the APPswe/PS1dE9 mouse model. Because astrocytes are key players in the pathogenesis of AD, we studied here if and how ES affects astrocytes in wildtype (WT) and APP/PS1 mice and how these relate to the previously reported amyloid pathology and microglial profile. Methods: We induced ES by limiting nesting and bedding material from postnatal days (P) 2-9. We studied in WT mice (at P9, P30, and 6 months) and in APP/PS1 mice (at 4 and 10 months) (i) GFAP coverage, cell density, and complexity in hippocampus (HPC) and entorhinal cortex (EC); (ii) hippocampal gene expression of astrocyte markers; and (iii) the relationship between astrocyte, microglia, and amyloid markers. Results: In WT mice, ES increased GFAP coverage in HPC subregions at P9 and decreased it at 10 months. APP/PS1 mice at 10 months exhibited both individual cell as well as clustered GFAP signals. APP/PS1 mice when compared to WT exhibited reduced total GFAP coverage in HPC, which is increased in the EC, while coverage of the clustered GFAP signal in the HPC was increased and accompanied by increased expression of several astrocytic genes. While measured astrocytic parameters in APP/PS1 mice appear not be further modulated by ES, analyzing these in the context of ES-induced alterations to amyloid pathology and microglial shows alterations at both 4 and 10 months of age. Conclusions: Our data suggest that ES leads to alterations to the astrocytic response to amyloid-β pathology.

2018

1. Early-life stress does not aggravate spatial memory or the process of hippocampal neurogenesis in adult and middle-aged APP/PS1 mice

   Lianne Hoeijmakers, Anna Amelianchik, Fleur Verhaag, Janssen Kotah, Paul J. Lucassen, and Aniko Korosi

   Frontiers in Aging Neuroscience, Mar 2018

   Abs DOI

   Life-time experiences are thought to influence the risk to develop the neurodegenerative disorder Alzheimer’s disease (AD). In particular, early-life stress (ES) may modulate the onset and progression of AD. There is recent evidence by our group and others that AD-related neuropathological progression and the associated neuroimmune responses are modulated by ES in the classic APPswe/PS1dE9 mouse model for AD. We here extend our previous study on ES media ted modulation of neuropathology and neuroinflammation and address in the same cohort of mice whether ES accelerates and/or aggravates AD-induced cognitive decline and alterations in the process of adult hippocampal neurogenesis (AHN), a form of brain plasticity. Chronic ES was induced by limiting bedding and nesting material during the first postnatal week and is known to induce cognitive deficits by 4 months in wild type (WT) mice. The onset of cognitive decline in APP/PS1 mice generally starts around 6 months of age. We here tested mice at ages 2-4 months to study acceleration and at ages 8-10 months for aggravation of the APP/PS1 phenotype. ES-exposed WT and APP/PS1 mice were able to perform the object recognition (ORT) and location tasks (OLT) at 2 months of age. Interestingly, at 3 months, ES induced impairments in the performance of the OLT in WT, but not in APP/PS1 mice. APP/PS1 mice exhibited alterations in hippocampal cell proliferation and differentiation, but ES exposure did not further change this. At 9 months, APP/PS1 mice exhibited impaired performance in the Morris Water Maze (MWM) task, as well as reductions in markers of the AHN process, which were not further modulated by ES exposure. In addition, we observed a so far unreported hyperactivity in ES-exposed mice at 8 months of age, which hampered assessment of cognitive functions in the ORT and OLT. In conclusion, while ES has been reported to modulate AD neuropathology and neuroinflammation before, it failed to accelerate or aggravate the decline in cognition or the process of AHN in APP/PS1 mice at ages 2-4 and 8-10 months. Future studies are needed to unravel how ES might affect the vulnerability to develop AD.