Mouse models of central nervous system ageing

Ageing is accompanied by decreased overall fitness and performance. Studying brain ageing in humans is challenging due to limited or no access to healthy tissue, limited opportunities for interventions and complicated confounding factors. The generation of mouse ageing models with uniform genetic backgrounds significantly contributed to understanding (brain) ageing at the molecular level. Research has focused on evolutionarily conserved mechanisms or pathways that control ageing to facilitate data extrapolation to humans. Understanding how these pathways contribute to pathological ageing may help us understand human central nervous system (CNS) ageing and assist in the development of possible therapeutic targets. In this review, we focus on the functional consequences and pathological changes in the CNS of ageing mouse models

Microglia morphotyping in the adult mouse CNS using hierarchical clustering on principal components reveals regional heterogeneity but no sexual dimorphism

Microglia are the resident macrophages of the central nervous system (CNS) and play a pivotal role in immune surveillance and CNS homeostasis. Morphological transitions in microglia are indicative for local changes in the CNS microenvironment and serve as a proxy for the detection of alterations in the CNS, both in health and disease. Current strategies to ‘measure’ microglia combine advanced morphometrics with clustering approaches to identify and categorize microglia morphologies. However, these studies are labor intensive and clustering approaches are often subject to relevant feature selection bias. Here, we provide a morphometrics pipeline with user-friendly computational tools for image segmentation, automated feature extraction and morphological categorization of microglia by means of hierarchical clustering on principal components (HCPC) without the need for feature inclusion criteria. With this pipeline we provide new and detailed insights in the distribution of microglia morphotypes across sixteen CNS regions along the rostro-caudal axis of the adult C57BL/6J mouse CNS. Although regional variations in microglia morphologies were evident, we found no evidence for male–female dimorphism at any CNS region investigated, indicating that - by and large - microglia in adult male and female mice are morphometrically indistinguishable. Taken together, our newly developed pipeline provides valuable tools for objective and unbiased identification and categorization of microglia morphotypes and can be applied to any CNS (disease) model.</p

The Netherlands Neurogenetics Database (NND)

Introducing the Netherlands Neurogenetics Database (NND) website, a joint effort between the Netherlands Brain Bank (NBB) and the University Medical Center Groningen (UMCG). The goal with the NND-website is to offer convenient access to meticulously processed and refined clinical-pathological summaries derived from NBB donors. This resource aims to foster collaborative research across various neurodegenerative and psychiatric diseases by facilitating cross-diagnostic investigations. Our platform encompasses a diverse array of features, including advanced filtering options and visualization tools that parallel the approaches employed in our most recent publication (Mekkes et al., 2022)

The Netherlands Neurogenetics Database (NND)

Introducing the Netherlands Neurogenetics Database (NND) website, a joint effort between the Netherlands Brain Bank (NBB) and the University Medical Center Groningen (UMCG). The goal with the NND-website is to offer convenient access to meticulously processed and refined clinical-pathological summaries derived from NBB donors. This resource aims to foster collaborative research across various neurodegenerative and psychiatric diseases by facilitating cross-diagnostic investigations. Our platform encompasses a diverse array of features, including advanced filtering options and visualization tools that parallel the approaches employed in our most recent publication (Mekkes et al., 2022)

The Netherlands Neurogenetics Database (NND)

Introducing the Netherlands Neurogenetics Database (NND) website, a joint effort between the Netherlands Brain Bank (NBB) and the University Medical Center Groningen (UMCG). The goal with the NND-website is to offer convenient access to meticulously processed and refined clinical-pathological summaries derived from NBB donors. This resource aims to foster collaborative research across various neurodegenerative and psychiatric diseases by facilitating cross-diagnostic investigations. Our platform encompasses a diverse array of features, including advanced filtering options and visualization tools that parallel the approaches employed in our most recent publication (Mekkes et al., 2022)

The Netherlands Neurogenetics Database (NND)

Introducing the Netherlands Neurogenetics Database (NND) website, a joint effort between the Netherlands Brain Bank (NBB) and the University Medical Center Groningen (UMCG). The goal with the NND-website is to offer convenient access to meticulously processed and refined clinical-pathological summaries derived from NBB donors. This resource aims to foster collaborative research across various neurodegenerative and psychiatric diseases by facilitating cross-diagnostic investigations. Our platform encompasses a diverse array of features, including advanced filtering options and visualization tools that parallel the approaches employed in our most recent publication (Mekkes et al., 2022)

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis

Prevention of microgliosis halts early memory loss in a mouse model of Alzheimer's disease

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline, the neuropathological formation of amyloid-beta (Aβ) plaques and neurofibrillary tangles. The best cellular correlates of the early cognitive deficits in AD patients are synapse loss and gliosis. In particular, it is unclear whether the activation of microglia (microgliosis) has a neuroprotective or pathological role early in AD. Here we report that microgliosis is an early mediator of synaptic dysfunction and cognitive impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We found that the appearance of microgliosis, synaptic dysfunction and behavioral impairment coincided with increased soluble Aβ42 levels, and occurred well before the presence of Aβ plaques. Inhibition of microglial activity by treatment with minocycline (MC) reduced gliosis, synaptic deficits and cognitive impairments at early pathological stages and was most effective when provided preventive, i.e., before the onset of microgliosis. Interestingly, soluble Aβ levels or Aβ plaques deposition were not affected by preventive MC treatment at an early pathological stage (4 months) whereas these were reduced upon treatment at a later stage (6 months). In conclusion, this study demonstrates the importance of early-stage prevention of microgliosis on the development of cognitive impairment in APP/PS1 mice, which might be clinically relevant in preventing memory loss and delaying AD pathogenesis

Neurovascular dysfunction in GRN-associated frontotemporal dementia identified by single-nucleus RNA sequencing of human cerebral cortex

Frontotemporal dementia (FTD) is the second most prevalent form of early-onset dementia, affecting predominantly frontal and temporal cerebral lobes. Heterozygous mutations in the progranulin gene (GRN) cause autosomal-dominant FTD (FTD-GRN), associated with TDP-43 inclusions, neuronal loss, axonal degeneration and gliosis, but FTD-GRN pathogenesis is largely unresolved. Here we report single-nucleus RNA sequencing of microglia, astrocytes and the neurovasculature from frontal, temporal and occipital cortical tissue from control and FTD-GRN brains. We show that fibroblast and mesenchymal cell numbers were enriched in FTD-GRN, and we identified disease-associated subtypes of astrocytes and endothelial cells. Expression of gene modules associated with blood–brain barrier (BBB) dysfunction was significantly enriched in FTD-GRN endothelial cells. The vasculature supportive function and capillary coverage by pericytes was reduced in FTD-GRN tissue, with increased and hypertrophic vascularization and an enrichment of perivascular T cells. Our results indicate a perturbed BBB and suggest that the neurovascular unit is severely affected in FTD-GRN