Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

Frost, Georgia; Jonas, Lauren A.; Li, Yueming

doi:10.3389/fnagi.2019.00337

Cited by 69 publications

(57 citation statements)

References 332 publications

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“…This result is consistent with past findings where the brain's immune system has been indicated as a major component of AD pathogenesis 60,61 . Additionally, MAPKs, enzymes that play critical roles in cellular signaling, have also been implicated as accelerators of AD development 62 .…”

Section: Discussionsupporting

confidence: 93%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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In spite of evidence of females having a greater lifetime risk of developing Alzheimer's Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls. Gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features revealed an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia 1,2 . It is pathologically characterized by the deposition of extracellular amyloid β (Aβ) and intracellular tau, otherwise referred to as plaques and neurofibrillary tangles, respectively 3-5 . AD is also marked by neuronal loss, impaired neurotransmitter signaling, neuroinflammation, and dysregulation of neuronal metabolism and immune response in the central nervous system 6-8 . AD prevalence increases dramatically with age, where the majority of cases are in individuals above the age of 65 1,9 . Although AD was identified more than a century ago 10 , its cause and pathophysiology are not fully understood, and there are no available treatments that aid in halting or reversing the disease 11 . Accordingly, it is of high priority to tackle AD, as it is projected to triple in incidence by 2050 as a consequence of population aging 6,8,12 and, to date, has no disease-modifying therapies.While the exact cause and pathophysiology remain unknown, a number of mutations and genetic risk factors have been identified as associated with AD. Apolipoprotein E (apoE) is the most common genetic risk factor for late onset AD 8,13-18 . ApoE is a lipid binding protein, that plays a central role in lipid transport and metabolism. It is highly expressed in the brain, and is important for maintaining neuronal membranes during inflammation and damage. In humans, apoE has three isoforms, apoE2, apoE3, and apoE4, which are encoded by the three alleles, ε2, ε3, and ε4, of the apoE gene, respectively. The ε2 isoform has been shown to be protective against AD, while the ε4 isoform (apoE4) is associated with increasing the risk and lowering the age of onset for developing late onset AD in a gene dose-dependent manner 19,20 . Specifically, one copy of the ε4 isoform confers a 3 to 4-fold increased risk and 7 year decrease in age of onset, while two copies confers a 12 to 15-fold increased r...

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Section: Discussionsupporting

confidence: 93%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

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“…Our characterization of brain transcriptomic signatures revealed, among upregulated genes in the brains of both females and males with AD, an enrichment of pathways related to components of the innate and adaptive immune systems as well as the MAPK signaling pathway. This result is consistent with past ndings where the brain's immune system has been indicated as a major component of AD pathogenesis 56,57 . Additionally, MAPKs, enzymes that play critical roles in cellular signaling, have also been implicated as accelerators of AD development 58 .…”

Section: Discussionsupporting

confidence: 93%

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

Paranjpe

Belonwu

Wang

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the United States. In spite of evidence of females having a greater lifetime risk of developing Alzheimer’s Disease (AD) and greater apolipoprotein E4-related (apoE4) AD risk compared to males, molecular signatures underlying these findings remain elusive. Methods: We took a meta-analysis approach to study gene expression in the brains of 1,084 AD patients and age-matched controls and whole blood from 645 AD patients and age-matched controls in seven independent datasets. Sex-specific gene expression patterns were investigated through use of gene-based, pathway-based and network-based approaches. The ability of a sex-specific AD gene expression signature to distinguish Alzheimer’s disease from healthy controls was assessed using a linear support vector machine model. Cell type deconvolution from whole blood gene expression data was performed to identify differentially regulated cells in males and females with AD.Results: Strikingly gene-expression, network-based analysis and cell type deconvolution approaches revealed a consistent immune signature in the brain and blood of female AD patients that was absent in males. In females, network-based analysis revealed a coordinated program of gene expression involving several zinc finger nuclease genes related to Herpes simplex viral infection whose expression was modulated by the presence of the apolipoprotein ε4 allele. Interestingly, this gene expression program was missing in the brains of male AD signature. Cell type deconvolution identified an increase in neutrophils and naïve B cells and a decrease in M2 macrophages, memory B cells, and CD8+ T cells in AD samples compared to controls in females. Interestingly, among males with AD, no significant differences in immune cell proportions compared to controls were observed. Machine learning-based classification of AD using gene expression from whole blood in addition to clinical features produced an improvement in classification accuracy upon stratifying by sex, achieving an AUROC of 0.91 for females and 0.80 for males. Conclusions: These results help identify sex and apoE4 genotype-specific transcriptomic signatures of AD and underscore the importance of considering sex in the development of biomarkers and therapeutic strategies for AD.

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“…IH analyses of cortical tissue with pan-microglia marker Iba and activated phagocytic microglia marker CD68 both showed that microglia in Brap cKONPC cortices were de-ramified, amoeboid-like, and activated ( Figure 4E). To confirm neuroinflammation, we examined the expression of several key inflammatory molecules implicated in human NDs (Dewachter et al, 2002;Frost et al, 2019;Newcombe et al, 2018;Sarlus and Heneka, 2017) and our RNA-seq data by RT-qPCR. These include C1q, TNFα, TGFβ1, and Trem2, which were all shown to be upregulated significantly in the cortical tissue of 3-month Brap cKONPC mice relative to that of the age-matched WT and/or control mice ( Figure 4F).…”

Section: Enhanced Neuroinflammation and Neurodegeneration In Brap Ckomentioning

confidence: 99%

Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration

Guo¹,

Chomiak²,

Yun

et al. 2020

Preprint

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Aging is an intricate process that is characterized by multiple hallmarks including stem cell exhaustion, genome instability, epigenome alteration, impaired proteostasis, and cellular senescence. While each of these is detrimental at the cellular level, it remains unclear how they are interconnected to cause systemic organ deterioration. Here we show that abrogating Brap, a BRCA1 associated protein, results in cellular senescence with persistent DNA double-strand breaks and elevation of histone H2A mono- and poly-ubiquitination (H2Aub). The high H2Aub initiates proteasome-dependent histone proteolysis, leading to global epigenetic alteration, ubiquitinated protein accumulation, and senescence reinforcement. When these defects occur in mice carrying Brap deletions in cerebral cortical neural progenitors or postnatal neurons, they accelerate brain aging, induce neurodegeneration, and shorten lifespan. As we show H2Aub is also increased in human brain tissues of Alzheimer disease, these data together suggest that chromatin aberrations mediated by H2Aub act as a nexus of multiple aging hallmarks.

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Friend, Foe or Both? Immune Activity in Alzheimer’s Disease

Cited by 69 publications

References 332 publications

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer’s Disease

Sex-Specific Cross Tissue Meta-Analysis Identifies Immune Dysregulation in Women with Alzheimer's Disease

Histone H2A ubiquitination resulting from Brap loss of function connects multiple aging hallmarks and accelerates neurodegeneration

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