Microglia contribute to the propagation of Aβ into unaffected brain tissue

d’Errico, Paolo; Ziegler‐Waldkirch, Stephanie; Aires, Vanessa; Hoffmann, Philippe; Mezö, Charlotte; Erny, Daniel; Monasor, Laura Sebastián; Liebscher, Sabine; Ravi, Vidhya; Joseph, Kevin; Schnell, Oliver; Kierdorf, Katrin; Staszewski, Ori; Tahirović, Sabina; Prinz, Marco; Meyer‐Luehmann, Melanie

doi:10.1038/s41593-021-00951-0

Cited by 112 publications

(92 citation statements)

References 33 publications

(41 reference statements)

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“…Cell adhesion is relevant for structural integrity and cell barrier formation (Sumigray and Lechler, 2015). Therefore, this impaired microglial adhesion function may reduce the microglia barrier build-up around Aβ plaques and promote microglial Aβ propagation in Piezo1 MGKO ; FAD mice as a new study confirms that microglia contribute to Aβ propagation into unaffected brain regions in vivo (d’Errico et al, 2022). In summary, Piezo1-mediated mechanical responses are required for microglial phagocytosis and compaction of the Aβ plaque, limiting Aβ pathology in the brain.…”

Section: Discussionmentioning

confidence: 77%

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Jin

Zhu

Yang

et al. 2022

Preprint

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SummaryThe pathology of Alzheimer’s disease (AD) is associated with the extracellular amyloid-β (Aβ) plaques that perturb the mechanical properties of brain tissue. Microglia sense and integrate biochemical cues in their local microenvironment, intimate linking with AD progress. However, neither the microglial mechanosensing pathway nor its impact on AD pathogenesis is well studied. Here, we showed that the mechanosensitive ion channel Piezo1 is increased in microglia upon stiffness stimuli of Aβ fibrils. The upregulation of Piezo1 in Aβ plaque-associated microglia was observed in AD mouse models and human patients. Microglia lacking Piezo1 disturbed microglial clustering, phagocytosis, and compaction of Aβ plaques, resulting in the exacerbation of Aβ and neurodegenerative pathologies in AD. Conversely, pharmacological activation of Piezo1 ameliorated brain Aβ burden and cognitive impairment in the 5×FAD mouse. Together, our results reveal Piezo1, as a mechanosensor of Aβ fibrils stiffness in microglia, could represent a promising therapeutic target for AD.

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Section: Discussionmentioning

confidence: 77%

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Jin

Zhu

Yang

et al. 2022

Preprint

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“… 36 Accordingly, some studies have presented evidence, stating that microglial activation might propagate Aβ formation in the brain, acting as a carrier through which the plaques could migrate into the unaffected areas of the brain. 37 Nevertheless, studies suggest that many types of microglia were activated at the time of a pathogenesis inside the brain, counteracting to one another, in terms of being proinflammatory and anti‐inflammatory. 38 Interestingly, growing evidence suggest that microglial activation as a result of stem cell administration, was more in favor of anti‐inflammation, rather than being proinflammatory.…”

Section: Discussionmentioning

confidence: 99%

Adipose tissue‐derived stem cells as a potential candidate in treatment of Alzheimer's disease: A systematic review on preclinical studies

Neishaboori

Eshraghi

Asl

et al. 2022

Pharmacology Res & Perspec

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In recent years, numerous investigations have evaluated the efficacy of adipose tissue‐derived stem cells (ADSCs) and their exosome transplantation in managing Alzheimer's disease (AD) in different animal models. However, there are still many contradictions among the studies that hinder reaching a reliable conclusion. Therefore, we aimed to systematically review the existing evidence regarding the efficacy of ADSCs administration in treatment of AD. The systematic search was conducted in the databases of Medline (via PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in Google and Google scholar, to find articles published until March 13, 2021. Preclinical studies were included and two independent reviewers summarized the eligible papers. Ten articles were included in our review. The treatment strategies varied between isolated ADSC, ADSCs exosomes, ADSCs conditioned medium, and combination therapy (ADSCs plus conditioned medium in one study, and ADSCs plus melatonin in another study). Overview of the included articles showed promising results of ADSCs and its conditioned medium/exosome administration in animal models of AD. These studies showed significant learning and memory improvements through ADSCs and their conditioned medium/exosome administration in animal models of AD. In addition, the application of ADSCs reduced the amyloid‐beta plaque deposits in the hippocampus and neocortex of these animals. Based on the aforementioned evidence, studies have suggested potential beneficial effects of ADSCs in the treatment of AD, particularly through decreasing the size of Aβ plaques and improvement of cognitive deficits. Further investigations regarding the subject are encouraged to achieve more accurate conclusions.

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“…Nevertheless, the propagation of Aβ seeds by passive diffusion cannot be ruled out [43]. Finally, several studies support that microglia play an important role in Aβ seeding and plaque formation [49][50][51].…”

Section: Aggregation and Prion-like Spreading Mechanismsmentioning

confidence: 99%

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

Sánchez-Varo

Mejias‐Ortega

Fernandez-Valenzuela

et al. 2022

IJMS

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Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery.

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Microglia contribute to the propagation of Aβ into unaffected brain tissue

Cited by 112 publications

References 33 publications

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Microglial Piezo1 senses Aβ fibrils stiffness to restrict Alzheimer’s disease

Adipose tissue‐derived stem cells as a potential candidate in treatment of Alzheimer's disease: A systematic review on preclinical studies

Transgenic Mouse Models of Alzheimer’s Disease: An Integrative Analysis

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