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

Kater, Mandy S.J.; Huffels, Christiaan F. M.; Oshima, Takuya; Renckens, Niek S.; Middeldorp, Jinte; Boddeke, Erik; Smit, August B.; Eggen, Bart J. L.; Hol, Elly M.; Verheijen, Mark H. G.

doi:10.1016/j.bbi.2022.10.009

Cited by 15 publications

(11 citation statements)

References 74 publications

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“…The animals were sacrificed 4 h post-shock (delayed shock, DS), a timepoint for which we previously showed alterations in proteins expressed in PAPs upon fear memory consolidation ( Rao-Ruiz et al, 2015 ; Sapkota et al, 2022 ). We found impaired contextual fear memory present in APP/PS1 mice at the age of 3 months ( Figure 2A ) which is in line with earlier reports by our group ( Végh et al, 2014 ; Kater et al, 2022 ). To note, we continued our analyses in 4 month old mice.…”

Section: Resultssupporting

confidence: 93%

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Kater

Badia‐Soteras

Weering

et al. 2023

Front. Cell. Neurosci.

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IntroductionAstrocyte-synapse bi-directional communication is required for neuronal development and synaptic plasticity. Astrocytes structurally interact with synapses using their distal processes also known as leaflets or perisynaptic astrocytic processes (PAPs). We recently showed that these PAPs are retracted from hippocampal synapses, and involved in the consolidation of fear memory. However, whether astrocytic synaptic coverage is affected when memory is impaired is unknown.MethodsHere, we describe in detail an electron microscopy method that makes use of a large number of 2D images to investigate structural astrocyte-synapse interaction in paraformaldehyde fixed brain tissue of mice.Results and discussionWe show that fear memory-induced synaptic activation reduces the interaction between the PAPs and the presynapse, but not the postsynapse, accompanied by retraction of the PAP tip from the synaptic cleft. Interestingly, this retraction is absent in the APP/PS1 mouse model of Alzheimer’s disease, supporting the concept that alterations in astrocyte-synapse coverage contribute to memory processing.

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Section: Resultssupporting

confidence: 93%

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Kater

Badia‐Soteras

Weering

et al. 2023

Front. Cell. Neurosci.

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“…Our current data further suggest these alterations occur specifically in the synapses of APP/PS1 mice, accompanied by a decrease in pre‐synaptic mitochondria, as also found in the temporal cortex of AD patients 61 . Interestingly, while ultrastructural changes to both synaptic mitochondria and synaptic vesicle have been described in post mortem human AD brains, 49 we show here for the first time that synaptic mitochondrial changes are already present at an early disease stage (pre‐plaque formation 15 ), in APP/PS1 mice, without other ultrastructural synaptic changes. This indicates that mitochondrial changes may precede changes in the number of synaptic vesicles found in more advanced stages of AD 49,62,63 .…”

Section: Discussionsupporting

confidence: 81%

“…Correspondingly, while ES had minimal effects on synaptosomes from early pathology (4 months) APP/PS1 mice (despite similar proteins and pathways being dysregulated in both groups), it resulted in large alterations at advanced pathological stage (10 months). Furthermore, APP/PS1 mice exhibited early synaptic changes to amyloid‐processing proteins such as App and Ncstn by 4 months, in line with alterations to microgliosis and behavior evident around this age, 15,16 that progressively worsen with age 13 . In ES‐exposed APP/PS1 mice, these progressively affected proteins in synaptosomes seemed differentially affected, suggesting that ES exposure alters the trajectory of the APP/PS1 phenotype, in a way that is both age‐ and pathological‐stage‐dependent.…”

Section: Discussionmentioning

confidence: 68%

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Kotah,

Kater,

Brosens

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONEarly‐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.METHODSWe 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.RESULTSThe 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.DISCUSSIONOur 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.

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“…Our studies underline the current opinion that, although classical microglia morphometrics provides elaborate and detailed information on microglia size and shape, it is not sufficient to identify and discriminate microglial subtypes in a morphologically heterogenous population. We have shown here that clustering on PCs provides an effective approach to morphotype microglia without the need for relevant feature selection (see also Heng et al, (2021); Kater et al, (2023);Zhang et al, (2021)). The sensitivity of our pipeline was demonstrated by its ability to identify microglia subtypes across sixteen CNS regions, both white and gray matter, and its ability to detect even subtle differences in microglia morphotype distributions between CNS regions.…”

Section: A Pipeline For Microglia Morphometrics and Objective Morphol...mentioning

confidence: 88%

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

Weering

Nijboer

Brummer

et al. 2023

Glia

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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 userfriendly 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.

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

Cited by 15 publications

References 74 publications

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Electron microscopy analysis of astrocyte-synapse interactions shows altered dynamics in an Alzheimer’s disease mouse model

Early‐life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

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

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