The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

Hur, Ji-Yeun; Frost, Georgia; Wu, Xinwei; Crump, Christina J.; Pan, Si; Wong, Eitan; Barros, Marilia; Li, Thomas; Nie, Pengju; Zhai, Yujia; Wang, Jen Chyong; Tcw, Julia; Guo, Lei; McKenzie, Andrew; Ming, Chi; Zhou, Xianxiao; Wang, Minghui; Sagi, Yotam; Renton, Alan E.; Esposito, Bianca; Kim, Yong; Sadleir, Katherine R.; Trinh, Ivy; Rissman, Robert A.; Vassar, Robert; Zhang, Bin; Johnson, Douglas S.; Masliah, Eliezer; Greengard, Paul; Goate, Alison; Li, Yueming

doi:10.1038/s41586-020-2681-2

Cited by 270 publications

(253 citation statements)

References 60 publications

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“…On the other hand, we observe that soluble A 1-42 increases at 6 months, coinciding with the rise in neuroinflammation and the onset of the tauopathy. Recent reports have indicated that inflammatory cytokines can increase -secretase activity in neurons, producing elevated A 1-42 (Alasmari et al 2018;Hur et al 2020), which is perfectly in line with our model. This supports the use of anti-inflammatory agents at the early stages as a preventive strategy to the proteinopathy as recently reinforced (Hampel et al 2020).…”

Section: Progressive Proteinopathysupporting

confidence: 92%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2020

Preprint

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BackgroundAlzheimer’s disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. To date, very few mouse models reproduce the pathophysiological progression of sporadic AD, while the majority of studies have employed transgenic animals reproducing the familial form.MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL).ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD shows a general tendency of the genes to decline except for GFAP.ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-AD, with progressive tau hyperphosphorylation, changes in microglia morphology, and gene reprogramming reflecting the increased neuroinflammation and the loss of neuronal functionality seen to some extent in humans.

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Section: Progressive Proteinopathysupporting

confidence: 92%

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Bathini

Dupanloup

Zenaro

et al. 2020

Preprint

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“…On the other hand, we observe that soluble A 1-42 increases at 6 months, coinciding with the rise in neuroin ammation and the onset of the tauopathy. Recent reports have indicated that in ammatory cytokines can increase -secretase activity in neurons, producing elevated A 1-42 (Alasmari et al 2018;Hur et al 2020), which is perfectly in line with our model. This supports the use of anti-in ammatory agents at the early stages as a preventive strategy to the proteinopathy as recently reinforced (Hampel et al 2020).…”

Section: Progressive Proteinopathysupporting

confidence: 92%

Systemic Inflammation Causes Microglial Dysfunction With a Mixed Ad-like Pathology

Bathini

Dupanloup

Zennaro

et al. 2020

Preprint

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BackgroundAlzheimer's disease (AD) is the primary cause of cognitive deficit in elderly humans. Late-onset AD (LOAD) is sporadic, multifactorial, non-Mendelian accounting at present for 95% of the cases in contrast to the genetic form. Risk factors for sporadic AD include Gene: Environment interactions. There is increasing evidence that lifestyle and environmental stress such as infection and chronic inflammation are underlying culprits of neurodegenerative dementia. Dementias that share or mimic pathological processes of AD include cerebrovascular diseases, Lewy body disease, TDP-43 proteinopathy. To date, very few mouse models reproduce the pathophysiological progression of mixed-vascular-AD, while the majority of studies have employed transgenic animals reproducing the familial form. MethodsWe have re-engineered the Polyinosinic:polycytidylic acid (PolyI:C) sterile infection model in wildtype C57Bl6 mice to obtain chronic low-grade systemic inflammation. We have conducted a cross-sectional analysis of aging PolyI:C and Saline control mice (3 months, 6 months, 9 months and 16 months), taking the hippocampus as a reference brain region, based on its vulnerability, and compared the brain aging phenotype to AD progression in humans with mild AD, severe AD and Controls (CTL), parallely in Vascular dementia (VaD) patient specimens.ResultsWe found that PolyI:C mice display both peripheral and central inflammation with a peak at 6 months, associated with memory deficits. The hippocampus is characterized by a pronounced and progressive tauopathy. In PolyI:C brains, microglia undergo aging-dependent morphological rearrangements progressively adopting a phagocytic phenotype. Transcriptomic analysis reveals a profound change in gene expression over the course of aging, with a peak in differential expression at 9 months. We confirm that the proinflammatory marker Lcn2 is one of the genes with the strongest upregulation in PolyI:C mice upon aging. Validation in brains from patients with increasing severity of AD and VaD shows a reproducibility of some gene targets in vascular dementia specimens rather than AD ones, in which only GFAP is strongly increased at the severe stages.ConclusionsThe PolyI:C model of sterile infection demonstrates that peripheral chronic inflammation is sufficient to cause neuropathological processes resembling a mixed-VaD-AD phenotype, with progressive tau hyperphosphorylation, changes in microglia morphology, astrogliosis and gene reprogramming reflecting increased neuroinflammation, vascular remodeling and the loss of neuronal functionality seen to some extent in humans.

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“…Not only does Aβ have antiviral activity, but its production may be controlled by the innate immunity protein, interferoninduced transmembrane protein 3 (IFITM3), which upregulates the activity of γ-secretase, resulting in the increased generation of Aβ peptide (Hur et al, 2020). Furthermore, deletion of IFITM3 in the 5xFAD mouse AD model resulted in reduced Aβ plaque formation, and IFITM3 expression was found to increase with aging and in mouse models expressing familial AD genes (Hur et al, 2020). IFITM3 plays a role in preventing viral infection, and its expression is induced by pro-inflammatory cytokines (Bailey et al, 2014).…”

Section: Aβ Response To Virusesmentioning

confidence: 99%

Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

Brown

Radford

Hewitt

2020

Front. Mol. Neurosci.

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Amyloid plaques are a pathological hallmark of Alzheimer’s disease. The major component of these plaques are highly ordered amyloid fibrils formed by amyloid-β (Aβ) peptides. However, whilst Aβ amyloid fibril assembly has been subjected to detailed and extensive analysis in vitro, these studies may not reproduce how Aβ fibrils assemble in the brain. This is because the brain represents a highly complex and dynamic environment, and in Alzheimer’s disease multiple cofactors may affect the assembly of Aβ fibrils. Moreover, in vivo amyloid plaque formation will reflect the balance between the assembly of Aβ fibrils and their degradation. This review explores the roles of microglia as cofactors in Aβ aggregation and in the clearance of amyloid deposits. In addition, we discuss how infection may be an additional cofactor in Aβ fibril assembly by virtue of the antimicrobial properties of Aβ peptides. Crucially, by understanding the roles of microglia and infection in Aβ amyloid fibril assembly it may be possible to identify new therapeutic targets for Alzheimer’s disease.

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The innate immunity protein IFITM3 modulates γ-secretase in Alzheimer’s disease

Cited by 270 publications

References 60 publications

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Systemic inflammation causes microglial dysfunction with a mixed AD-like pathology

Systemic Inflammation Causes Microglial Dysfunction With a Mixed Ad-like Pathology

Modulation of β-Amyloid Fibril Formation in Alzheimer’s Disease by Microglia and Infection

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