The red-hot debate about transmissible Alzheimer's

Abbott, Alison

doi:10.1038/531294a

Cited by 16 publications

(6 citation statements)

References 13 publications

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“…Immunostaining for αSyn detection was performed on paraffin-embedded coronal tissue sections (6 µm, cut from blocks equilibrated to room temperature [RT]) at three different sectional planes: (1) in the midbrain at the level of the substantia nigra, (2) in the midbrain at the level of raphe nuclei/periaqueductal gray, and (3) in the medulla oblongata at the level of vestibular nuclei. At these sectional planes, entire brain sections were scrutinized for staining signals of pathological αSyn phosphorylated at serine 129 (pSer129 αSyn) in perikarya and processes of cells.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson’s disease

et al. 2021

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Cerebral deposition of abnormally aggregated α-synuclein (αSyn) is a neuropathological hallmark of Parkinson’s disease (PD). PD-associated αSyn (αSynPD) aggregates can act as proteinaceous nuclei (“seeds”) able of self-templated propagation. Since this is strikingly reminiscent to properties of proteinaceous infectious particles (prions), lessons learned from prion diseases suggest to test whether transferred αSynPD can propagate and induce neurological impairments or disease in a new host. Two studies that addressed this question provided divergent results. Intracerebral (i.c.) injection of Lewy body extracts from PD patients caused cerebral αSyn pathology, as well as nigrostriatal neurodegeneration, of wild-type mice and macaques, with the mice also showing motor impairments (Recasens et al. 2014, Ann Neurol 75:351–362). In contrast, i.c. transmission of homogenates from PD brains did not stimulate, after “> 360” days post-injection (dpi), pathological αSyn conversion or clinical symptoms in transgenic TgM83+/− mice hemizygously expressing mutated (A53T) human αSyn (Prusiner et al. 2015, PNAS 112:E5308–E5317). To advance the assessment of possible αSynPD hazards by providing further data, we examined neuropathological and clinical effects upon i.c. transmission of brain, stomach wall and muscle tissue as well as blood from PD patients in TgM83+/− mice up to 612 dpi. This revealed a subtle, yet distinctive stimulation of localized αSyn aggregation in the somatodendritic compartment and dystrophic neurites of individual or focally clustered cerebral neurons after challenge with brain and stomach wall homogenates. No such effect was observed with transmitted blood or homogenized muscle tissue. The detected stimulation of αSyn aggregation was not accompanied by apparent motor impairments or overt neurological disease in TgM83+/− mice. Our study substantiated that transmitted αSynPD seeds, including those from the stomach wall, are able to propagate in new mammalian hosts. The consequences of such propagation and potential safeguards need to be further investigated.

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Section: Immunohistochemistrymentioning

confidence: 99%

Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson’s disease

et al. 2021

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“…Thus, de novo fibrillogenesis from soluble VL domains can be rapid and requires misfolding of the VL, allowing structured self-association into thermodynamically stable multimers that act as templates, or seeds, for the recruitment of additional VL domains. Template-mediated seeding is a universal paradigm in amyloid-related pathologies that underlies the proposed transmissibility of amyloid diseases [46–50]. …”

Section: Discussionmentioning

confidence: 99%

Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils—A metric for predicting amyloid propensity

et al. 2017

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BackgroundMonoclonal free light chain (LC) proteins are present in the circulation of patients with immunoproliferative disorders such as light chain (AL) amyloidosis and multiple myeloma (MM). Light chain-associated amyloid is a complex pathology composed of proteinaceous fibrils and extracellular matrix proteins found in all patients with AL and in ~10–30% of patients who presented with MM. Amyloid deposits systemically in multiple organs and tissues leading to dysfunction and ultimately death. The overall survival of patients with amyloidosis is worse than for those with early stage MM.Methods and findingsWe have developed a sensitive binding assay quantifying the recruitment of full length, patient-derived LC proteins by synthetic amyloid fibrils, as a method for studying their amyloidogenic potential. In a survey of eight urinary LC, both AL and MM-associated proteins were recruited by synthetic amyloid fibrils; however, AL-associated LC bound significantly more efficiently (p < 0.05) than did MM LCs. The LC proteins used in this study were isolated from urine and presumed to represent a surrogate of serum free light chains.ConclusionThe binding of LC to synthetic fibrils in this assay accurately differentiated LC with amyloidogenic propensity from MM LC that were not associated with clinical amyloid disease. Notably, the LC from a MM patient who subsequently developed amyloid behaved as an AL-associated protein in the assay, indicating the possibility for identifying MM patients at risk for developing amyloidosis based on the light chain recruitment efficacy. With this information, at risk patients can be monitored more closely for the development of amyloidosis, allowing timely administration of novel, amyloid-directed immunotherapies—this approach may improve the prognosis for these patients.

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“…Prion disease affects the nervous system of many mammals, including humans [90]. Indeed, because of the huge similarity of the protein aggregation, some scientists do not discard that other NDDs like AD, ALS and other syndromes are caused (and transmitted) by prion-like proteins [91,92].…”

Section: Neurodegenerative Diseases (Ndds)mentioning

confidence: 99%

Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments

Sales

Prandi

Castro

et al. 2019

IJMS

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The brain has a unique biological complexity and is responsible for important functions in the human body, such as the command of cognitive and motor functions. Disruptive disorders that affect this organ, e.g. neurodegenerative diseases (NDDs), can lead to permanent damage, impairing the patients’ quality of life and even causing death. In spite of their clinical diversity, these NDDs share common characteristics, such as the accumulation of specific proteins in the cells, the compromise of the metal ion homeostasis in the brain, among others. Despite considerable advances in understanding the mechanisms of these diseases and advances in the development of treatments, these disorders remain uncured. Considering the diversity of mechanisms that act in NDDs, a wide range of compounds have been developed to act by different means. Thus, promising compounds with contrasting properties, such as chelating agents and metal-based drugs have been proposed to act on different molecular targets as well as to contribute to the same goal, which is the treatment of NDDs. This review seeks to discuss the different roles and recent developments of metal-based drugs, such as metal complexes and metal chelating agents as a proposal for the treatment of NDDs.

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The red-hot debate about transmissible Alzheimer's

Cited by 16 publications

References 13 publications

Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson’s disease

Transmissible α-synuclein seeding activity in brain and stomach of patients with Parkinson’s disease

Differential recruitment efficacy of patient-derived amyloidogenic and myeloma light chain proteins by synthetic fibrils—A metric for predicting amyloid propensity

Recent Developments in Metal-Based Drugs and Chelating Agents for Neurodegenerative Diseases Treatments

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