Association between APOE genotype and microglial cell morphology

Abstract

APOE is the largest genetic risk factor for late-onset Alzheimer disease (AD) with E4 conferring an increased risk for AD compared to E3. The ApoE protein can impact diverse pathways in the brain including neuroinflammation but the precise impact of ApoE isoforms on inflammation remains unknown. As microglia are a primary source of neuroinflammation, this study determined whether ApoE isoforms have an impact on microglial morphology and activation using immunohistochemistry and digital analyses. Analysis of ionized calcium-binding adaptor molecule 1 (Iba1) immunoreactivity indicated greater microglial activation in both the hippocampus and superior and middle temporal gyrus (SMTG) in dementia participants versus non-demented controls. Further, only an increase in activation was seen in E3-Dementia participants in the entire SMTG, whereas in the grey matter of the SMTG, only a diagnosis of dementia impacted activation. Specific microglial morphologies showed a reduction in ramified microglia in the dementia group. For rod microglia, a reduction was seen in E4-Control patients in the hippocampus whereas in the SMTG an increase was seen in E4-Dementia patients. These findings suggest an association between ApoE isoforms and microglial morphologies and highlight the importance of considering ApoE isoforms in studies of AD pathology.

Female mice display sex-specific differences in cerebrovascular function and subarachnoid haemorrhage-induced injury

“…The histological procedures have been described previously. 4 , 14 Briefly, brains were fixed via aortic perfusion with 10% buffered formalin. Samples were then embedded in paraffin blocks.…”

“…Each slide was digitally imaged at 20× magnification with an Olympus VS-120 slide scanner and loaded into the HALO software: the HALO Object Colocalization FL v2.1.4 module quantified the number of Iba/F4/80 double-positive cells and the HALO Microglial Activation FL v1.0.6 module assessed morphologic activation, using previously established threshold settings for differentiating activated from non-activated microglia. 14 …”

A small-molecule TLR4 antagonist reduced neuroinflammation in female E4FAD mice

“…There are limitations in the extent that we can conclude TLR4 and/or neuroinflammation specifically contributes to neural dysfunction in female APOE4 mice. In fact, studies have shown that microglial activation and neuroinflammation are greater with APOE4 than APOE3 in males using APOE knock in mice [ 14 , 114 – 116 ], FAD mice [ 11 , 15 , 43 ], and AD patients [ 117 , 118 ]. Indeed, it is important to note that we found that IAXO-101 lowered microglial number and reactivity in older male E4FAD mice, although performance in the Morris water maze test was not affected.…”