The expanding realm of prion phenomena in neurodegenerative disease

Frost, Bess; Diamond, Marc I.

doi:10.4161/pri.3.2.8754

Cited by 31 publications

(32 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent results cast a new light on the role of insoluble extracellular t as a transmissible agent spreading t pathology throughout the brain in "prion-like fashion" (22)(23)(24). Multiple lines of evidence also indicate that extracellular t protein may play an important role in AD neuroinflammation.…”

mentioning

confidence: 99%

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Kováč

Žilka

Kazmerova

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

Neuroinflammation plays a key role in the pathogenesis of Alzheimer’s disease and related tauopathies. We have previously shown that expression of nonmutated human truncated τ (151-391, 4R), derived from sporadic Alzheimer's disease, induced neurofibrillary degeneration accompanied by microglial and astroglial activation in the brain of transgenic rats. The aim of the current study was to determine the molecular mechanism underlying innate immune response induced by misfolded truncated τ. We found that purified recombinant truncated τ induced morphological transformation of microglia from resting into the reactive phenotype. Simultaneously, truncated τ caused the release of NO, proinflammatory cytokines (IL-1β, IL-6, TNF-α), and tissue inhibitor of metalloproteinase-1 from the mixed glial cultures. Notably, when the pure microglial culture was activated with truncated τ, it displayed significantly higher levels of the proinflammatory cytokines, suggesting a key role of microglia in the τ-mediated inflammatory response. Molecular analysis showed that truncated τ increased the mRNA levels of three MAPKs (JNK, ERK1, p38β) and transcription factors AP-1 and NF-κB that ultimately resulted in enhanced mRNA expression of IL-1β, IL-6, TNF-α, and NO. Our results showed for the first time, to our knowledge, that misfolded truncated protein τ is able to induce innate immune response via a MAPK pathway. Consequently, we suggest that misfolded truncated protein τ represents a viable target for immunotherapy of Alzheimer’s disease.

show abstract

mentioning

confidence: 99%

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Kováč

Žilka

Kazmerova

et al. 2011

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Neurodegenerative disorders characterized by protein misfolding and aggregation, including ALS, commonly display phenotypic diversity, such as variation in the age of onset, the rate of neuronal dysregulation, and the area of the nervous system affected (Armstrong et al 2000;Goedert et al 2001;Frost and Diamond 2009;Williamson et al 2009). Although the molecular origins of such phenotypic diversity are complex and may differ between diseases, in recent years it has been shown that protein aggregates, including amyloid fibrils, exhibit extensive structural heterogeneity both in vivo and in vitro (Berryman et al 2009;Frost and Diamond 2009).…”

Section: Protein Aggregation Heterogeneity and Disease Complexitymentioning

confidence: 99%

“…Although the molecular origins of such phenotypic diversity are complex and may differ between diseases, in recent years it has been shown that protein aggregates, including amyloid fibrils, exhibit extensive structural heterogeneity both in vivo and in vitro (Berryman et al 2009;Frost and Diamond 2009). Not only do fibrils formed by different amino acid sequences adopt conformations that differ in length and twist, but the structure of fibrils formed by the same sequence can vary depending on solution conditions (Berryman et al 2009).…”

Section: Protein Aggregation Heterogeneity and Disease Complexitymentioning

confidence: 99%

“…Prion amyloid fibrils can differ in stability, surface charge and degree of polypeptide incorporation into the amyloid core, differences that may play a large role in determining rate of prion replication and the strength of the disease phenotype (Verges et al 2011). In recent years, evidence for conformational diversity, or different strains, of protein aggregates has also been described for non-infectious protein conformational disorders such as Alzheimer's, Parkinson's, Frontal Temporal Dementia, and ALS (Frost and Diamond 2009;Furukawa et al 2010). The proteins linked to many of these diseases are natively disordered, and so can easily sample different conformations, which may facilitate aggregation via multiple pathways.…”

Section: Protein Aggregation Heterogeneity and Disease Complexitymentioning

confidence: 99%

See 1 more Smart Citation

Folding and Aggregation of Cu, Zn-Superoxide Dismutase

Broom¹,

Primmer²,

Rumfeldt³

et al. 2012

Amyotrophic Lateral Sclerosis

View full text Add to dashboard Cite

“…It is believed that internalization of amyloid aggregates and subsequent replication within the cell are crucial to the spread of amyloid pathology between cells and within tissues [25]. In cellular models, aggregates of the tau protein can spread between cells and accelerate tau aggregation in neighboring cells [28,29].…”

mentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

View full text Add to dashboard Cite

Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

show abstract

The expanding realm of prion phenomena in neurodegenerative disease

Cited by 31 publications

References 30 publications

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Misfolded Truncated Protein τ Induces Innate Immune Response via MAPK Pathway

Folding and Aggregation of Cu, Zn-Superoxide Dismutase

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Contact Info

Product

Resources

About