The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

Walker, Lary C.; Schelle, Juliane; Jucker, Mathias

doi:10.1101/cshperspect.a024398

Cited by 78 publications

(62 citation statements)

References 117 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, (iv) prion-like or templated propagation of Tau pathology has been consistently and reproducibly shown in in vitro and in vivo models, highlighting a self-propagating effect of Tau pathology once initiated [3, 12, 24–26, 30–33, 36, 37, 44, 49, 50, 56, 62, 77, 84, 89, 96, 97]. Prion-like propagation of Tau pathology thereby presents as a compelling mechanism for the progressive and characteristic development of Tau pathology, remarkably strong correlated with symptom progression in AD.…”

Section: Introductionmentioning

confidence: 99%

Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

et al. 2019

View full text Add to dashboard Cite

Brains of Alzheimer’s disease patients are characterized by the presence of amyloid plaques and neurofibrillary tangles, both invariably associated with neuroinflammation. A crucial role for NLRP3–ASC inflammasome [NACHT, LRR and PYD domains-containing protein 3 (NLRP3)–Apoptosis-associated speck-like protein containing a CARD (ASC)] in amyloid-beta (Aβ)-induced microgliosis and Aβ pathology has been unequivocally identified. Aβ aggregates activate NLRP3–ASC inflammasome (Halle et al. in Nat Immunol 9:857–865, 2008) and conversely NLRP3–ASC inflammasome activation exacerbates amyloid pathology in vivo (Heneka et al. in Nature 493:674–678, 2013), including by prion-like ASC-speck cross-seeding (Venegas et al. in Nature 552:355–361, 2017). However, the link between inflammasome activation, as crucial sensor of innate immunity, and Tau remains unexplored. Here, we analyzed whether Tau aggregates acting as prion-like Tau seeds can activate NLRP3–ASC inflammasome. We demonstrate that Tau seeds activate NLRP3–ASC-dependent inflammasome in primary microglia, following microglial uptake and lysosomal sorting of Tau seeds. Next, we analyzed the role of inflammasome activation in prion-like or templated seeding of Tau pathology and found significant inhibition of exogenously seeded Tau pathology by ASC deficiency in Tau transgenic mice. We furthermore demonstrate that chronic intracerebral administration of the NLRP3 inhibitor, MCC950, inhibits exogenously seeded Tau pathology. Finally, ASC deficiency also decreased non-exogenously seeded Tau pathology in Tau transgenic mice. Overall our findings demonstrate that Tau-seeding competent, aggregated Tau activates the ASC inflammasome through the NLRP3–ASC axis, and we demonstrate an exacerbating role of the NLRP3–ASC axis on exogenously and non-exogenously seeded Tau pathology in Tau mice in vivo. The NLRP3–ASC inflammasome, which is an important sensor of innate immunity and intensively explored for its role in health and disease, hence presents as an interesting therapeutic approach to target three crucial pathogenetic processes in AD, including prion-like seeding of Tau pathology, Aβ pathology and neuroinflammation.Electronic supplementary materialThe online version of this article (10.1007/s00401-018-01957-y) contains supplementary material, which is available to authorized users.

show abstract

Section: Introductionmentioning

confidence: 99%

Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

et al. 2019

View full text Add to dashboard Cite

show abstract

“…AD is believed to exist in a number of subtypes, with experimental data indicating that different conformations of Ab and tau misfolded protein might underlie distinct pathologic phenotypes, a phenomenon possibly analogous to the multiple strains of the prion diseases (5)(6)(7)(8). In addition, the misfolded proteins in AD act as seeds for "prion-like" conversion of normally folded protein to abnormal conformations (9,10). Similar to prions, the misfolded proteins Ab and tau are able to induce the pathologic conformational changes in their respective naive proteins and through this mechanism spread within the CNS and occasionally from the periphery to the brain (11).…”

mentioning

confidence: 99%

Unravelling the glial response in the pathogenesis of Alzheimer's disease

2018

View full text Add to dashboard Cite

Alzheimer's disease is a progressive, incurable neurodegenerative disease targeting specific neuronal populations within the brain while neighboring neurons appear unaffected. The focus for defining mechanisms has therefore been on the pathogenesis in affected neuronal populations and developing intervention strategies to prevent their cell death. However, there is growing recognition of the importance of glial cells in the development of pathology. Determining exactly how glial cells are involved in the disease process and the susceptibility of the aging brain provides unprecedented challenges. The present review examines recent studies attempting to unravel the glial response during the course of disease and how this action may dictate the outcome of neurodegeneration. The importance of regional heterogeneity of glial cells within the CNS during healthy aging and disease is examined to understand how the glial cells may contribute to neuronal susceptibility or resilience during the neurodegenerative process.—Alibhai, J. D., Diack, A. B., Manson, J. C. Unravelling the glial response in the pathogenesis of Alzheimer's disease. 32, 5766–5777 (2018). http://www.fasebj.org

show abstract

“…Recently, comprehensive reviews on this fascinating subject have been published to which refer for in-depth details and specific references (Tatarnikova et al, 2015; Ugalde et al, 2016; Walker et al, 2016). Aβ, like PrP, may undergo conformational changes assuming a tertiary structure rich in β sheets that promotes the self-assembly of the protein in oligomeric and fibrillar aggregates with neurotoxic properties (Haass and Selkoe, 2007; Klein, 2013).…”

Section: Alzheimer's Disease As a Prion-like Diseasementioning

confidence: 99%

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

Toni¹,

Massimino

Mario

et al. 2017

Front. Neurosci.

View full text Add to dashboard Cite

Metal ions are key elements in organisms' life acting like cofactors of many enzymes but they can also be potentially dangerous for the cell participating in redox reactions that lead to the formation of reactive oxygen species (ROS). Any factor inducing or limiting a metal dyshomeostasis, ROS production and cell injury may contribute to the onset of neurodegenerative diseases or play a neuroprotective action. Transmissible spongiform encephalopathies (TSEs), also known as prion diseases, are a group of fatal neurodegenerative disorders affecting the central nervous system (CNS) of human and other mammalian species. The causative agent of TSEs is believed to be the scrapie prion protein PrPSc, the β sheet-rich pathogenic isoform produced by the conformational conversion of the α-helix-rich physiological isoform PrPC. The peculiarity of PrPSc is its ability to self-propagate in exponential fashion in cells and its tendency to precipitate in insoluble and protease-resistance amyloid aggregates leading to neuronal cell death. The expression “prion-like diseases” refers to a group of neurodegenerative diseases that share some neuropathological features with prion diseases such as the involvement of proteins (α-synuclein, amyloid β, and tau) able to precipitate producing amyloid deposits following conformational change. High social impact diseases such as Alzheimer's and Parkinson's belong to prion-like diseases. Accumulating evidence suggests that the exposure to environmental metals is a risk factor for the development of prion and prion-like diseases and that metal ions can directly bind to prion and prion-like proteins affecting the amount of amyloid aggregates. The diet, source of metal ions but also of natural antioxidant and chelating agents such as polyphenols, is an aspect to take into account in addressing the issue of neurodegeneration. Epidemiological data suggest that the Mediterranean diet, based on the abundant consumption of fresh vegetables and on low intake of meat, could play a preventive or delaying role in prion and prion-like neurodegenerative diseases. In this review, metal role in the onset of prion and prion-like diseases is dealt with from a nutritional, cellular, and molecular point of view.

show abstract

The Prion-Like Properties of Amyloid-β Assemblies: Implications for Alzheimer's Disease

Cited by 78 publications

References 117 publications

Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

Aggregated Tau activates NLRP3–ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo

Unravelling the glial response in the pathogenesis of Alzheimer's disease

Metal Dyshomeostasis and Their Pathological Role in Prion and Prion-Like Diseases: The Basis for a Nutritional Approach

Contact Info

Product

Resources

About