ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy

Seo, Dong Oh; O’Donnell, David; Jain, Nimansha; Ulrich, Jason D.; Herz, Jasmin; Li, Yuhao; Lemieux, Mackenzie; Cheng, Jiye; Hu, Hao; Serrano, Javier Remolina; Bao, Xiaoyi; Franke, Emily; Karlsson, Maria; Meier, Martin; Deng, Su; Desai, Chandni; Dodiya, Hemraj B.; Lelwala‐Guruge, Janaki; Handley, Scott A.; Kipnis, Jonathan; Sisodia, Sangram S.; Gordon, Jeffrey I.; Holtzman, David M.

doi:10.1126/science.add1236

Cited by 110 publications

(98 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…At euthanasia at 40 weeks, the GM manipulation had resulted in a marked reduction in tau pathology and neurodegeneration depending on ApoE isoform. Astrocytes and microglia were observed to be in a more homeostatic-like state, indicating that GM significantly influenced neuroinflammation and tau-pathology in this model (Seo et al, 2023). Epidemiological studies show that patients with the above listed brain disorders and diseases, typically carry a dysbiotic gut microbiome often characterized by lack of microbial richness (alpha diversity) and skewness (beta diversity) compared to healthy people.…”

Section: Introductionmentioning

confidence: 82%

Getting closer to modeling the gut-brain axis using induced pluripotent stem cells

Hall

Bendtsen

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The gut microbiome (GM), the gut barrier, and the blood-brain barrier (BBB) are key elements of the gut-brain axis (GBA). The advances in organ-on-a-chip and induced pluripotent stem cell (iPSCs) technology might enable more physiological gut-brain-axis-on-a-chip models. The ability to mimic complex physiological functions of the GBA is needed in basic mechanistic research as well as disease research of psychiatric, neurodevelopmental, functional, and neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. These brain disorders have been associated with GM dysbiosis, which may affect the brain via the GBA. Although animal models have paved the way for the breakthroughs and progression in the understanding of the GBA, the fundamental questions of exactly when, how, and why still remain unanswered. The research of the complex GBA have relied on equally complex animal models, but today’s ethical knowledge and responsibilities demand interdisciplinary development of non-animal models to study such systems. In this review we briefly describe the gut barrier and BBB, provide an overview of current cell models, and discuss the use of iPSCs in these GBA elements. We highlight the perspectives of producing GBA chips using iPSCs and the challenges that remain in the field.

show abstract

Section: Introductionmentioning

confidence: 82%

Getting closer to modeling the gut-brain axis using induced pluripotent stem cells

Hall

Bendtsen

2023

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Previous studies report that SCFAs were decreased in the feces and brain of APP/PS1 mice compared with WT mice (24). SCFAs can modulate Aβ plaques in the brain (49), astrocytic gene expression (67), expression of tight junction proteins (68), directly act on afferent vagal bers (69), and induce ApoE-associated Tauopathy (70). In our study, butyric acid, one of the SCFAs, decreased in AD Tg and the ADWT mice compared to WT mice both in feces and brain tissues of mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transmission of Alzheimer's Disease-Associated Microbiota Dysbiosis and its Impact on Cognitive Function: Evidence from Mouse Models and Human Patients

Zhang

Shen

Liufu

et al. 2023

Preprint

View full text Add to dashboard Cite

Spouses of Alzheimer’s disease (AD) patients are at higher risk of developing AD dementia, but the reasons and underlying mechanism are unknown. One potential factor is gut microbiota dysbiosis, which has been associated with AD. However, it remains unclear whether the gut microbiota dysbiosis can be transmitted to non-AD individuals and contribute to the development of AD pathogenesis and cognitive impairment. The present study found that co-housing wild-type mice with AD transgenic mice or giving them AD transgenic mice feces caused AD-associated gut microbiota dysbiosis, Tau phosphorylation, and cognitive impairment. Gavage with Lactobacillus and Bifidobacterium restored these changes. The oral and gut microbiota of AD patient partners resembled that of AD patients but differed from healthy controls, indicating the transmission of oral and gut microbiota and its impact on cognitive function. The underlying mechanism of these findings includes that the butyric acid-mediated acetylation of GSK3β at lysine 15 regulated its phosphorylation at serine 9, consequently impacting Tau phosphorylation. These results provide insight into a potential link between gut microbiota dysbiosis and AD and underscore the need for further research in this area.

show abstract

“…89 Interestingly, Aβ or phosphorylated tau deposition attenuation by ABX treatment was observed only in male mice, reflecting possible sex differences in microglial responses. 90,91 Overall, age-and disease-associated changes in gut microbiota composition and metabolism might serve as therapeutic targets for AD, although detailed mechanisms remain to be elucidated.…”

Section: Brain-periphery Interactions In Ad Pathogenesismentioning

confidence: 99%

“…Conversely, gut microbiota depletion by an antibiotic cocktail (ABX) reduced Aβ load in APP/PS1 mice, which was diminished by microglial depletion with colony‐stimulating factor 1 receptor inhibitor 89 . Interestingly, Aβ or phosphorylated tau deposition attenuation by ABX treatment was observed only in male mice, reflecting possible sex differences in microglial responses 90,91 . Overall, age‐ and disease‐associated changes in gut microbiota composition and metabolism might serve as therapeutic targets for AD, although detailed mechanisms remain to be elucidated.…”

Section: Brain–periphery Interactions In Ad Pathogenesismentioning

confidence: 99%

Multifactorial glial responses and their contributions to Alzheimer's disease continuum

Hijioka

Manabe

Saito

2023

Clinical & Exp Neuroim

View full text Add to dashboard Cite

Alzheimer's disease (AD) is the most common neurocognitive disorder. Various factors are intricately intertwined before clinical symptoms appear, although both amyloid‐β peptide deposition and neurofibrillary tangle formation (i.e. pathological hallmarks of the AD brain) are established. Among such factors, glial responses have been increasingly recognized as important roles in the progression of these pathologies and viewed as one component of the AD continuum. However, the detailed molecular and cellular mechanisms of glial function underlying AD pathogenesis remain to be elucidated. Recent studies showed that peripheral immunity, gut microbiota or environmental factors influence brain pathophysiologies through communication with glial cells in the brain. This disease complexity makes understanding AD etiology difficult and hinders the development of effective therapeutic strategies to tackle this disease. Conversely, aged patients often suffer from multiple – not a single – diseases as multimorbidity, and AD pathogenesis might be related to pathologies caused by other diseases. Hence, investigating AD as a systemic disease has become critical for identifying therapeutic interventions. This review aimed to summarize current knowledge on AD research and share perspectives for understanding glial functions regarding AD pathophysiology.

show abstract

ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy

Cited by 110 publications

References 42 publications

Getting closer to modeling the gut-brain axis using induced pluripotent stem cells

Getting closer to modeling the gut-brain axis using induced pluripotent stem cells

Transmission of Alzheimer's Disease-Associated Microbiota Dysbiosis and its Impact on Cognitive Function: Evidence from Mouse Models and Human Patients

Multifactorial glial responses and their contributions to Alzheimer's disease continuum

Contact Info

Product

Resources

About