Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Kellogg, Collyn M.; Pham, Kevin D.; Machalinski, Adeline H.; Porter, Hunter; Blankenship, Harris E.; Tooley, Kyla B.; Stout, Michael B.; Rice, Heather C.; Sharpe, Amanda L.; Beckstead, Michael J.; Chucair-Elliott, Ana J.; Ocañas, Sarah R.; Freeman, Willard M.

doi:10.1007/s11357-023-00859-6

Cited by 3 publications

(2 citation statements)

References 117 publications

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“…Age of Tam induction does not affect the trajectory of age-related changes in the brain: Once NuTRAP allele induction was determined to be equivalent in both ages of Tam induction and collection, we asked whether timing of Tam induction can affect biological endpoints of importance. We and others have identified significant transcriptional changes in hippocampal microglia with aging 40,48,49 . We compared gene expression data from the TRAP positive fractions of old mice following early Tam induction (n=7, 7 females) and old mice following late Tam induction (n=5, 5 females) to young mice following early Tam induction (n=5, 5 females) to analyze differential gene expression (One way ANOVA, Benjamini Hochberg Multiple Testing Correction q<0.1, Fold Change >|1.25|) with aging.…”

Section: Resultsmentioning

confidence: 67%

“…p16 Ink 4a is more associated with senescence and demonstrated a significant increase, consistent between induction ages while p19 Arf had smaller increases with age ( Figure 5D ). In our recent work, we have identified MHC-I components as upregulated with age in microglia from humans, mice, and rats 48 . To assess whether this result is recapitulated with the different induction ages, we analyzed expression of genes for MHC-I and their receptors with early and late Tam induction.…”

Section: Resultsmentioning

confidence: 99%

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Consistent specificity and efficiency of tamoxifen-mediated cre induction across ages

Kellogg,

Pham,

et al. 2023

Preprint

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Temporally controlling cre recombination through tamoxifen (Tam) induction has many advantages for biomedical research. Most studies report Tam induction at early post-natal/juvenile (<2 m.o.) mouse ages, but age-related neurodegeneration and aging studies can require cre induction in older mice (>12 m.o.). While anecdotally reported as problematic, there are no published comparisons of Tam mediated cre induction at early and late ages. Here, microglial-specific Cx3cr1creERT2 mice were crossed to a floxed NuTRAP reporter to compare cre induction at early (3-6 m.o.) and late (20 m.o.) ages. Specificity and efficiency of microglial labeling at 21-22 m.o. were identical in mice induced with Tam at 3-6 m.o. or 20 m.o. of age. Age-related microglial translatomic changes were also similar regardless of Tam induction age. Each cre and flox mouse line should be validated independently, however, these findings demonstrate that Tam-mediated cre induction can be performed even into older mouse ages.

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Section: Resultsmentioning

confidence: 67%

Section: Resultsmentioning

confidence: 99%

Consistent specificity and efficiency of tamoxifen-mediated cre induction across ages

Kellogg,

Pham,

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

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Specificity and efficiency of tamoxifen-mediated Cre induction is equivalent regardless of age

Kellogg,

Pham,

et al. 2023

iScience

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Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

Ocañas¹,

Pham²,

Cox³

et al. 2023

J Neuroinflammation

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Background Microglia, the brain’s principal immune cells, have been implicated in the pathogenesis of Alzheimer’s disease (AD), a condition shown to affect more females than males. Although sex differences in microglial function and transcriptomic programming have been described across development and in disease models of AD, no studies have comprehensively identified the sex divergences that emerge in the aging mouse hippocampus. Further, existing models of AD generally develop pathology (amyloid plaques and tau tangles) early in life and fail to recapitulate the aged brain environment associated with late-onset AD. Here, we examined and compared transcriptomic and translatomic sex effects in young and old murine hippocampal microglia. Methods Hippocampal tissue from C57BL6/N and microglial NuTRAP mice of both sexes were collected at young (5–6 month-old [mo]) and old (22–25 mo) ages. Cell sorting and affinity purification techniques were used to isolate the microglial transcriptome and translatome for RNA-sequencing and differential expression analyses. Flow cytometry, qPCR, and imaging approaches were used to confirm the transcriptomic and translatomic findings. Results There were marginal sex differences identified in the young hippocampal microglia, with most differentially expressed genes (DEGs) restricted to the sex chromosomes. Both sex chromosomally and autosomally encoded sex differences emerged with aging. These sex DEGs identified at old age were primarily female-biased and enriched in senescent and disease-associated microglial signatures. Normalized gene expression values can be accessed through a searchable web interface (https://neuroepigenomics.omrf.org/). Pathway analyses identified upstream regulators induced to a greater extent in females than in males, including inflammatory mediators IFNG, TNF, and IL1B, as well as AD-risk genes TREM2 and APP. Conclusions These data suggest that female microglia adopt disease-associated and senescent phenotypes in the aging mouse hippocampus, even in the absence of disease pathology, to a greater extent than males. This sexually divergent microglial phenotype may explain the difference in susceptibility and disease progression in the case of AD pathology. Future studies will need to explore sex differences in microglial heterogeneity in response to AD pathology and determine how sex-specific regulators (i.e., sex chromosomal or hormonal) elicit these sex effects.

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Microglial MHC-I induction with aging and Alzheimer’s is conserved in mouse models and humans

Cited by 3 publications

References 117 publications

Consistent specificity and efficiency of tamoxifen-mediated cre induction across ages

Consistent specificity and efficiency of tamoxifen-mediated cre induction across ages

Specificity and efficiency of tamoxifen-mediated Cre induction is equivalent regardless of age

Microglial senescence contributes to female-biased neuroinflammation in the aging mouse hippocampus: implications for Alzheimer’s disease

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