Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Crapser, Joshua; Arreola, Miguel A.; Tsourmas, Kate I; Green, Kim N.

doi:10.1038/s41423-021-00751-3

Cited by 82 publications

(95 citation statements)

References 342 publications

(561 reference statements)

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“…However, Aβ itself, but not tau, progressively impairs the capacity of these glial cells to eliminate damaged amyloid-containing presynaptic elements ( Sanchez-Mico et al, 2021 ). Besides, microglial cells are implicated in synaptic homeostasis as well, and the rate of maintenance/elimination of boutons or perineuronal nets might be altered due to amyloid exposition ( Hong et al, 2016 ; Crapser et al, 2020 , 2021 ). Soluble Aβ itself can induce synaptic alterations in the absence of plaques ( Lue et al, 1999 ; Dorostkar et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

et al. 2021

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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder characterized by initial memory impairments that progress to dementia. In this sense, synaptic dysfunction and loss have been established as the pathological features that best correlate with the typical early cognitive decline in this disease. At the histopathological level, post mortem AD brains typically exhibit intraneuronal neurofibrillary tangles (NFTs) along with the accumulation of amyloid-beta (Abeta) peptides in the form of extracellular deposits. Specifically, the oligomeric soluble forms of Abeta are considered the most synaptotoxic species. In addition, neuritic plaques are Abeta deposits surrounded by activated microglia and astroglia cells together with abnormal swellings of neuronal processes named dystrophic neurites. These periplaque aberrant neurites are mostly presynaptic elements and represent the first pathological indicator of synaptic dysfunction. In terms of losing synaptic proteins, the hippocampus is one of the brain regions most affected in AD patients. In this work, we report an early decline in spatial memory, along with hippocampal synaptic changes, in an amyloidogenic APP/PS1 transgenic model. Quantitative electron microscopy revealed a spatial synaptotoxic pattern around neuritic plaques with significant loss of periplaque synaptic terminals, showing rising synapse loss close to the border, especially in larger plaques. Moreover, dystrophic presynapses were filled with autophagic vesicles in detriment of the presynaptic vesicular density, probably interfering with synaptic function at very early synaptopathological disease stages. Electron immunogold labeling showed that the periphery of amyloid plaques, and the associated dystrophic neurites, was enriched in Abeta oligomers supporting an extracellular location of the synaptotoxins. Finally, the incubation of primary neurons with soluble fractions derived from 6-month-old APP/PS1 hippocampus induced significant loss of synaptic proteins, but not neuronal death. Indeed, this preclinical transgenic model could serve to investigate therapies targeted at initial stages of synaptic dysfunction relevant to the prodromal and early AD.

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Section: Discussionmentioning

confidence: 99%

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

et al. 2021

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“…With a focus on the hippocampus, as well as on cultured hippocampal neurons, electrophysiological alterations were observed when perineuronal nets were disrupted in vivo and in vitro [ 271 , 302 , 303 , 304 , 305 , 306 ]. Interestingly, there is a growing evidence that microglia are involved in the maintenance of perineuronal nets [ 307 ]. In disease models for Alzheimer’s and Huntington’s, a contribution of microglia to the loss of perineuronal nets could be proven [ 308 , 309 ].…”

Section: Interneuron-abnormalities In the Hippocampus Of Schizophreni...mentioning

confidence: 99%

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Wegrzyn

Juckel

Faissner

2022

IJMS

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Schizophrenia is a grave neuropsychiatric disease which frequently onsets between the end of adolescence and the beginning of adulthood. It is characterized by a variety of neuropsychiatric abnormalities which are categorized into positive, negative and cognitive symptoms. Most therapeutical strategies address the positive symptoms by antagonizing D2-dopamine-receptors (DR). However, negative and cognitive symptoms persist and highly impair the life quality of patients due to their disabling effects. Interestingly, hippocampal deviations are a hallmark of schizophrenia and can be observed in early as well as advanced phases of the disease progression. These alterations are commonly accompanied by a rise in neuronal activity. Therefore, hippocampal formation plays an important role in the manifestation of schizophrenia. Furthermore, studies with animal models revealed a link between environmental risk factors and morphological as well as electrophysiological abnormalities in the hippocampus. Here, we review recent findings on structural and functional hippocampal abnormalities in schizophrenic patients and in schizophrenia animal models, and we give an overview on current experimental approaches that especially target the hippocampus. A better understanding of hippocampal aberrations in schizophrenia might clarify their impact on the manifestation and on the outcome of this severe disease.

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“…We have consistently observed that elimination of microglia via colony stimulation factor 1 receptor (CSF1R) inhibitors 14 dramatically increases PNN coverage throughout the brain 15 – 18 . Furthermore, upon cessation of treatment with the CSF1R inhibitor PLX5622, microglia repopulate the brain and PNNs decrease back to basal levels 19 .…”

Section: Introductionmentioning

confidence: 99%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

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Microglia are subject to change in tandem with the endogenously generated biological oscillations known as our circadian rhythm. Studies have shown microglia harbor an intrinsic molecular clock which regulates diurnal changes in morphology and influences inflammatory responses. In the adult brain, microglia play an important role in the regulation of condensed extracellular matrix structures called perineuronal nets (PNNs), and it has been suggested that PNNs are also regulated in a circadian and diurnal manner. We sought to determine whether microglia mediate the diurnal regulation of PNNs via CSF1R inhibitor dependent microglial depletion in C57BL/6J mice, and how the absence of microglia might affect cortical diurnal gene expression rhythms. While we observe diurnal differences in microglial morphology, where microglia are most ramified at the onset of the dark phase, we do not find diurnal differences in PNN intensity. However, PNN intensity increases across many brain regions in the absence of microglia, supporting a role for microglia in the regulation of PNNs. Here, we also show that cortical diurnal gene expression rhythms are intact, with no cycling gene changes without microglia. These findings demonstrate a role for microglia in the maintenance of PNNs, but not in the maintenance of diurnal rhythms.

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Microglia as hackers of the matrix: sculpting synapses and the extracellular space

Cited by 82 publications

References 342 publications

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Plaque-Associated Oligomeric Amyloid-Beta Drives Early Synaptotoxicity in APP/PS1 Mice Hippocampus: Ultrastructural Pathology Analysis

Structural and Functional Deviations of the Hippocampus in Schizophrenia and Schizophrenia Animal Models

Cortical diurnal rhythms remain intact with microglial depletion

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