Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Bundy, Joseph L.; Vied, Cynthia; Badger, Crystal Dawn; Nowakowski, Richard S.

doi:10.1002/cne.24551

Cited by 77 publications

(68 citation statements)

References 68 publications

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“…This result is largely consistent with other emerging findings of surprisingly poor correlation between mRNA and protein levels among a variety of experimental systems [13,17,[53][54][55], including analyses of human postmortem brain tissue [18,19,56]. In one notable study relevant to AD, a similar fraction (40%) of differentially expressed transcripts in the 5XFAD amyloid precursor protein transgenic mouse showed discordant changes in the proteome [57]. Many discordant changes likely reflect regulatory feedback interactions that maintain protein homeostasis.…”

Section: Discussionsupporting

confidence: 86%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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BackgroundTau neurofibrillary tangle pathology characterizes Alzheimer's disease and other neurodegenerative tauopathies. Brain gene expression profiles can reveal mechanisms; however, few studies have systematically examined both the transcriptome and proteome or differentiated Tau-versus agedependent changes. MethodsPaired, longitudinal RNA-sequencing and mass-spectrometry were performed in a Drosophila model of tauopathy, based on pan-neuronal expression of human wildtype Tau (Tau WT ) or a mutation causing frontotemporal dementia (Tau R406W ). Tau-induced, differentially expressed transcripts and proteins were examined cross-sectionally or using linear regression and adjusting for age. Hierarchical clustering was performed to highlight network perturbations, and we examined overlaps with human brain gene expression profiles in tauopathy. ResultsTau WT induced 1,514 and 213 differentially expressed transcripts and proteins, respectively. Tau R406W had a substantially greater impact, causing changes in 5,494 transcripts and 697 proteins. There was a ~70% overlap between age-and Tau-induced changes and our analyses reveal pervasive bi-directional interactions. Strikingly, 42% of Tau-induced transcripts were discordant in the proteome, showing opposite direction of change. Tau-responsive gene expression networks strongly implicate innate immune activation, despite the absence of microglia in flies. Cross-species analyses pinpoint human brain gene perturbations specifically triggered by Tau pathology and/or aging, and further differentiate between disease amplifying and protective changes. ConclusionsOur results comprise a powerful, cross-species functional genomics resource for tauopathy, revealing Tau-mediated disruption of gene expression, including dynamic, age-dependent interactions between the brain transcriptome and proteome. BackgroundThe Microtubule Associated Protein Tau (MAPT/Tau) aggregates to form neurofibrillary tangle pathology in Alzheimer's disease (AD) and other neurodegenerative tauopathies characterized by progressive cognitive and/or motor disability, including progressive supranuclear palsy (PSP), corticobasal degeneration, chronic traumatic encephalopathy, and certain forms of frontotemporal dementia (FTD) [1,2]. Rare mutations in the MAPT gene cause familial FTD, which is also characterized by prominent neurofibrillary tangle deposition [3][4][5]. Based on this genetic evidence, along with results from cellular and animal models [6,7], Tau is a critical mediator of age-related neurodegeneration and a causal link among this diverse group of neurologic disorders. While the precise mechanisms of Tauinduced neuronal injury remain incompletely defined, progressive synaptic dysfunction and neuronal loss likely arises from a cascade of cellular derangements, including oxidative-and immune-mediated injury, altered proteostasis, and aberrant transcription and translation [6,8].RNA-sequencing (RNA-seq) makes possible comprehensive gene expression profiling of postmortem human brain tissue in AD and o...

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Section: Discussionsupporting

confidence: 86%

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Mangleburg

Yalamanchili

et al. 2020

Preprint

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“…Notably, even the youngest age group of 5XFAD mutant mice (3 months) displayed significant enrichment of genes containing 3' or 5' IREs compared to age-matched wild types. This is consistent with an enrichment of immune-related Hallmark gene sets that we observed in this age group (see Figure 7B) and with a previous transcriptome analysis suggesting immune activation in 5XFAD mice as early as 2-4 months [42]. UpSet plots of overlapping leading-edge genes suggest that the IRE responses due to aging and due to the 5XFAD transgenes may involve partially overlapping gene expression changes (Figure 8).…”

Section: Age-dependent Disruption Of Ire-driven Iron Homeostasis In Tsupporting

confidence: 91%

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Hin

Newman

Pederson

et al. 2020

Preprint

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Background: Iron trafficking and accumulation has been associated with Alzheimer's disease (AD) pathogenesis. However, the role of iron dyshomeostasis in early disease stages is uncertain. Currently, gene expression changes indicative of iron dyshomeostasis are not well characterised, making it difficult to explore these in existing datasets. Results: We identified sets of genes predicted to contain Iron Responsive Elements (IREs), and used these to explore iron dyshomeostasis responses in transcript datasets involving (1) cultured cells under iron overload and deficiency treatments, (2) post-mortem brain tissues from AD and other neuropathologies, (3) 5XFAD transgenic mice modelling AD pathologies, and (4) a zebrafish knock-in model of early-onset, familial AD (fAD). IRE gene sets were sufficiently sensitive to distinguish not only between iron overload and deficiency in cultured cells, but also between AD and other pathological brain conditions. Notably, we see changes in 3' IRE transcript abundance as amongst the earliest observable in zebrafish fAD-like brains and preceding other AD-typical pathologies such as inflammatory changes. Unexpectedly, while some 3' IRE transcripts show significantly increased stability under iron deficiency in line with current assumptions, many such transcripts instead show decreased stability, indicating that this is not a generalizable paradigm. Conclusions: Our results reveal iron dyshomeostasis as a likely early driver of fAD and as able to distinguish AD from other brain pathologies. Our work demonstrates how differences in the stability of IRE-containing transcripts can be used to explore and compare iron dyshomeostasis responses in different species, tissues, and conditions.

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“…In the original paper characterizing Tg6799 (5XFAD) pathology [35], female mice demonstrated increased levels of Aβ 42 and Aβ 40 compared to males. Bundy et al showed that this may be due to increased expression of the transgene in female 5XFAD mice [39]. Females also appear to have increased BACE1 activity, a β-secretase processing enzyme which cleaves pAPP and produces pathogenic Aβ fragments [40,41], ultimately leading to increased amyloid plaque burden compared to male 5XFAD mice [41,42].…”

Section: Introductionmentioning

confidence: 99%

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

et al. 2019

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Centella asiatica (CA) herb is a traditional medicine, long reputed to provide cognitive benefits. We have reported that CA water extract (CAW) treatment improves cognitive function of aged Alzheimer’s disease (AD) model Tg2576 and wild-type (WT) mice, and induces an NRF2-regulated antioxidant response in aged WT mice. Here, CAW was administered to AD model 5XFAD female and male mice and WT littermates (age: 7.6 +/ − 0.6 months), and object recall and contextual fear memory were tested after three weeks treatment. CAW’s impact on amyloid-β plaque burden, and markers of neuronal oxidative stress and synaptic density, was assessed after five weeks treatment. CAW antioxidant activity was evaluated via nuclear transcription factor (erythroid-derived 2)-like 2 (NRF2) and NRF2-regulated antioxidant response element gene expression. Memory improvement in both genders and genotypes was associated with dose-dependent CAW treatment without affecting plaque burden, and marginally increased synaptic density markers in the hippocampus and prefrontal cortex. CAW treatment increased Nrf2 in hippocampus and other NRF2 targets (heme oxygenase-1, NAD(P)H quinone dehydrogenase 1, glutamate-cysteine ligase catalytic subunit). Reduced plaque-associated SOD1, an indicator of oxidative stress, was observed in the hippocampi and cortices of CAW-treated 5XFAD mice. We postulate that CAW treatment leads to reduced oxidative stress, contributing to improved neuronal health and cognition.

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Sex‐biased hippocampal pathology in the 5XFAD mouse model of Alzheimer's disease: A multi‐omic analysis

Cited by 77 publications

References 68 publications

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Integrated analysis of the aging brain transcriptome and proteome in tauopathy

Iron Responsive Element (IRE)-mediated responses to iron dyshomeostasis in Alzheimer’s disease

Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice

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