Microglia‐specific <scp>ApoE</scp> knock‐out does not alter Alzheimer's disease plaque pathogenesis or gene expression

Henningfield, Caden M; Arreola, Miguel A.; Soni, Neelakshi; Spangenberg, Elizabeth E.; Green, Kim N.

doi:10.1002/glia.24105

Cited by 26 publications

(20 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As previously described 45 , sections were washed 3× 5 min in 1× PBS and immersed in normal serum blocking solution (5% normal serum + 0.2% Triton-X100 in 1× PBS) for 1 h. Tissue was then incubated overnight in primary antibody at the dilutions described above in normal serum blocking solution at 4 °C. The next day tissue sections were washed in 3× 5 min in 1× PBS before being placed in appropriate secondary antibody in normal serum blocking solution (1:200 for all species and wavelengths; Invitrogen) for 1 h. Tissue sections were then washed for 3× 5 min in 1× PBS before tissue was mounted and coverslipped.…”

Section: Methodsmentioning

confidence: 99%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Methodsmentioning

confidence: 99%

Cortical diurnal rhythms remain intact with microglial depletion

Barahona

Morabito

Swarup

et al. 2022

Sci Rep

Self Cite

View full text Add to dashboard Cite

show abstract

“…Whilst APOE deficiency in APP/PS1 mice was associated with reduced density of Aβ plaques, remaining plaques showed reduced compaction, a loss of microglial clustering around plaques, worsened NFD, and a significant downregulation of immunerelated genes (Ulrich et al, 2018) and others such as Itgax and Cst7-genes which are highly expressed in DAM (Keren-Shaul et al, 2017). Unexpectedly, the complete knock-out of microglia-specific APOE in 5×FAD mice did not alter plaque load, number of microglia, or clustering of microglia but was associated with increased average plaque size (Henningfield et al, 2022)-notably in this study, astroglial APOE is still present. The APOE ε4 allele contributes to the disruption of glial homeostatic functions (Fernandez et al, 2019).…”

Section: Genomic and Transcriptomic Signatures Of Microglia In Alzhei...mentioning

confidence: 87%

Synapses, Microglia, and Lipids in Alzheimer’s Disease

et al. 2022

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is characterised by synaptic dysfunction accompanied by the microscopically visible accumulation of pathological protein deposits and cellular dystrophy involving both neurons and glia. Late-stage AD shows pronounced loss of synapses and neurons across several differentially affected brain regions. Recent studies of advanced AD using post-mortem brain samples have demonstrated the direct involvement of microglia in synaptic changes. Variants of the Apolipoprotein E and Triggering Receptors Expressed on Myeloid Cells gene represent important determinants of microglial activity but also of lipid metabolism in cells of the central nervous system. Here we review evidence that may help to explain how abnormal lipid metabolism, microglial activation, and synaptic pathophysiology are inter-related in AD.

show abstract

“…For example, fibrillar amyloid plaques formed in Cre + mice with strongly reduced astrocytic apoE still contain apoE, which indicates the apoE present in plaques is likely coming from other cellular sources such as microglia. In fact, a recent study showed that the removal of endogenous murine apoE from microglia results in the formation of dense-core plaques that are larger in size; however, there was no change in the overall levels of Aβ plaque load [ 65 ].…”

Section: Discussionmentioning

confidence: 99%

Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis

Mahan

Wang

Bao

et al. 2022

Mol Neurodegeneration

View full text Add to dashboard Cite

Background One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, it is not fully known how apoE produced by specific cell types, such as astrocytes, contributes to amyloid pathology. Methods We utilized APOE knock-in mice capable of having APOE selectively removed from astrocytes in a tamoxifen-inducible manner and crossed them with the APP/PS1-21 mouse model of amyloidosis. We analyzed the changes to Aβ plaque levels and assessed the impact on cellular responses to Aβ plaques when astrocytic APOE is removed. Results Tamoxifen administration was capable of strongly reducing apoE levels in the brain by markedly reducing astrocyte apoE, while microglial apoE expression remained. Reduction of astrocytic apoE3 and apoE4 led to a large decrease in Aβ plaque deposition and less compact plaques. While overall Iba1+ microglia were unchanged in the cortex after reducing astrocyte apoE, the expression of the disease-associated microglial markers Clec7a and apoE were lower around amyloid plaques, indicating decreased microglial activation. Additionally, astrocyte GFAP levels are unchanged around amyloid plaques, but overall GFAP levels are reduced in the cortex of female apoE4 mice after a reduction in astrocytic apoE. Finally, while the amount of neuritic dystrophy around remaining individual plaques was increased with the removal of astrocytic apoE, the overall amount of cortical amyloid-associated neuritic dystrophy was significantly decreased. Conclusion This study reveals an important role of astrocytic apoE3 and apoE4 on the deposition and accumulation of Aβ plaques as well as on certain Aβ-associated downstream effects.

show abstract

Microglia‐specific ApoE knock‐out does not alter Alzheimer's disease plaque pathogenesis or gene expression

Cited by 26 publications

References 74 publications

Cortical diurnal rhythms remain intact with microglial depletion

Cortical diurnal rhythms remain intact with microglial depletion

Synapses, Microglia, and Lipids in Alzheimer’s Disease

Selective reduction of astrocyte apoE3 and apoE4 strongly reduces Aβ accumulation and plaque-related pathology in a mouse model of amyloidosis

Contact Info

Product

Resources

About