Antiviral Immune Response in Alzheimer’s Disease: Connecting the Dots

Roy, Ethan; Cao, Wei

doi:10.3389/fnins.2020.577744

Cited by 6 publications

(5 citation statements)

References 79 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In fact, recent studies investigating both human brain tissues and mouse models suggest that type 1 interferon responses drive neuro-inflammation and synapse loss in Alzheimer’s disease, thus perhaps supporting a causal role for viral or bacterial infection in development of Alzheimer’s disease. 37 , 38 Our results support this Pathogen Hypothesis but argue that the problem is internal; disrupted A-to-I editing leads to accumulation of potentially pathogenic quantities of unedited Alu dsRNAs triggering dsRNA sensors resulting in strong innate immune activation.…”

Section: Discussionsupporting

confidence: 63%

“… 36 Recent studies also demonstrate presence of ongoing chronic inflammatory responses in brains of people with Alzheimer’s disease suggesting that innate immune activation may contribute to Alzheimer’s disease pathogenesis. 37 , 38 As in studies described above, a source of innate immune activation may be loss of A-to-I editing and accumulation of Alu dsRNAs. Therefore, we sought to explore if A-to-I editing dysfunction existed in the human brain in Alzheimer’s disease and if so, determine if A-to-I editing dysfunction is present in multiple brain regions or localizes to specific brain regions.…”

Section: Introductionmentioning

confidence: 88%

See 1 more Smart Citation

Reduced RNA adenosine-to-inosine editing in hippocampus vasculature associated with Alzheimer’s disease

Crooke

Tossberg

Heinrich

et al. 2022

Brain Communications

View full text Add to dashboard Cite

Alzheimer’s disease is the most common form of dementia and recent studies identify a type 1 interferon response in Alzheimer’s disease possibly driving neuro-inflammation and other Alzheimer’s disease pathologies. Loss of adenosine-to-inosine editing of endogenous Alu RNAs results in accumulation of Alu double-stranded RNAs, activation of double-stranded RNA sensors, and induction of interferon and nuclear factor kappa B regulated genes. Here, we investigated if changes in adenosine-to-inosine editing were associated with presence of Alzheimer’s disease in total prefrontal cortex, total hippocampus, cortex vasculature, and hippocampus vasculature using available RNA-sequencing files. We found similar levels of Alu RNA adenosine-to-inosine editing in cortex and cortex vasculature from individuals with Alzheimer’s disease or normal cognition at the time of death and brain donation. We found modest and substantial loss of adenosine-to-inosine editing in hippocampus and hippocampus vasculature, respectively, in Alzheimer’s disease relative to normal cognition and increased expression of interferon and nuclear factor-kappa B regulated genes in hippocampus. Unedited Alu RNAs as found in Alzheimer’s disease hippocampus vasculature were potent innate immune activators while edited Alu RNAs as found in normal cognition hippocampus vasculature were weak innate immune activators. Taken together, our results support a model whereby loss of Alu RNA adenosine-to-inosine editing in hippocampus results in innate immune activation that may contribute to Alzheimer’s disease pathogenesis.

show abstract

Section: Discussionsupporting

confidence: 63%

Section: Introductionmentioning

confidence: 88%

Reduced RNA adenosine-to-inosine editing in hippocampus vasculature associated with Alzheimer’s disease

Crooke

Tossberg

Heinrich

et al. 2022

Brain Communications

View full text Add to dashboard Cite

show abstract

“…Therefore, it is plausible that IFN-I signaling perpetuates a feedforward loop for brain cell senescence, a scenario consistent with recent findings regarding accelerated aging driven by Stat1, the signaling mediator immediately downstream of IFN-I receptor, in progeria mice [ 38 ]. As IFN-I response has been pathogenically implicated in neurodegeneration [ 28 , 39 , 40 ], this innate immune axis could be a valid target for therapeutic intervention throughout the course of disease development.…”

Section: Main Textmentioning

confidence: 99%

Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging

Roy,

Li,

Saroukhani

et al. 2024

Mol Neurodegeneration

Self Cite

View full text Add to dashboard Cite

Background Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth. Methods To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters. Results We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Conclusions Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.

show abstract

“…These findings suggest that viral infection might contribute to the neuroinflammation and neuronal damage that occur in Alzheimer's disease [58,59]. Another study utilized single-cell sequencing to investigate the role of the gut microbiome in Alzheimer's disease.…”

Section: Ad Pathogenesis [151]mentioning

confidence: 99%

Unlocking the mysteries of Alzheimer’s disease: Role of single-cell sequencing in uncovering microbial infections

Singh,

Kaushik,

Gupta

et al. 2024

J App Biol Biotech

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterized by the accumulation of amyloid plaques and neurofibrillary tangles in the brain. Despite decades of research, the underlying causes of AD remain poorly understood. However, recent evidence suggests that microbial infections may play a role in the development and progression of AD. With the advent of single-cell sequencing (SCS) technology, researchers now have a powerful tool to study the microbial communities in AD brains at high resolution. This review article focuses on the latest research on the role of SCS in investigating the relationship between microbial infections and AD. By enabling the identification and characterization of specific microbial species and their interactions with host cells in AD brains, SCS has provided new insights into the complex microbial landscape of AD. Furthermore, this technology has the potential to impact the diagnosis and treatment of AD by revealing new targets for therapeutic intervention. Finally, we also discussed about the challenges, limitations, ethical, and translational considerations of SCS technology, as well as future research directions in this area. The potential impact of SCS on understanding microbial infections in AD is significant, and it may lead to the development of new therapies and preventive measures for this devastating disease. In conclusion, this review highlights the important role that SCS plays in advancing our understanding of the complex microbial communities in AD and their potential involvement in disease pathogenesis.

show abstract

Antiviral Immune Response in Alzheimer’s Disease: Connecting the Dots

Cited by 6 publications

References 79 publications

Reduced RNA adenosine-to-inosine editing in hippocampus vasculature associated with Alzheimer’s disease

Reduced RNA adenosine-to-inosine editing in hippocampus vasculature associated with Alzheimer’s disease

Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging

Unlocking the mysteries of Alzheimer’s disease: Role of single-cell sequencing in uncovering microbial infections

Contact Info

Product

Resources

About