Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Li, He; Kim, Chae; Haldiman, Tracy; Sigurdson, Christina J.; Nyström, Sofie; Nilsson, K. Peter R.; Cohen, Mark L.; Wısnıewskı, Thomas; Hammarström, Per; Safar, Jiri

doi:10.1016/j.jbc.2021.101267

Cited by 29 publications

(40 citation statements)

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“…Both studies reported phenotypic variations associated with strain morphology. Phenotypic variations include variations in incubation time, symptoms, degree of pathology as well as affected regions and cell types representing various pathological profiles (Lau et al, 2020 ; Liu et al, 2021 ). These findings support the notion of specific asyn strains causing distinct disease phenotypes.…”

Section: Alpha-synuclein and Strain Variabilitymentioning

confidence: 99%

“…Thus, the distinct conformation or “spectral fingerprint” of the ligand upon interaction with a certain asyn aggregate reflect the 3D structure of that asyn aggregate (Klingstedt and Nilsson, 2012 ; Gustafsson et al, 2021 ). These fluorescent LCO-ligands thus identify a broader subset of pathogenic protein aggregates than conventional ligands such as ThT, as they have been established as a class of ligands for superior recognition and spectral assignment of disease-associated protein aggregates, including different polymorphic Aβ (Ellingsen et al, 2013 ; Rasmussen et al, 2017 ; Calvo-Rodriguez et al, 2019 ; Lantz et al, 2020 ; Liu et al, 2021 ), asyn (Klingstedt et al, 2019 ; Shahnawaz et al, 2020 ) aggregates, as well as toxic and non-toxic polymorphic variants of insulin, both in vitro (Psonka-Antonczyk et al, 2012 ; Mori et al, 2021 ) and in patient biopsies (Yuzu et al, 2020 ).…”

Section: Luminescent Conjugated Oligothiophenes To Identify Different...mentioning

confidence: 99%

“…Thus, also in AD the variable phenotype amongst patients may be associated with the presence of different Aβ strains. Liu et al ( 2021 ) observed a high conformational diversity of Aβ in the neocortex of AD cases, with most distinct spectral profiles in the temporal cortex of cases with shorter disease duration, implicating distinct Aβ strains are responsible for more rapidly progressing AD. Moreover, Rasmussen et al ( 2017 ) observed distinct spectral fingerprints of different amyloid aggregates within a single end-stage AD brain.…”

Section: Luminescent Conjugated Oligothiophenes To Identify Different...mentioning

confidence: 99%

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Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

Just

Gram

Theologidis

et al. 2022

Front. Aging Neurosci.

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Pathogenic alpha-synuclein (asyn) aggregates are a defining feature of neurodegenerative synucleinopathies, which include Parkinson's disease, Lewy body dementia, pure autonomic failure and multiple system atrophy. Early accurate differentiation between these synucleinopathies is challenging due to the highly heterogeneous clinical profile at early prodromal disease stages. Therefore, diagnosis is often made in late disease stages when a patient presents with a broad range of motor and non-motor symptoms easing the differentiation. Increasing data suggest the clinical heterogeneity seen in patients is explained by the presence of distinct asyn strains, which exhibit variable morphologies and pathological functions. Recently, asyn seed amplification assays (PMCA and RT-QuIC) and conformation-specific ligand assays have made promising progress in differentiating between synucleinopathies in prodromal and advanced disease stages. Importantly, the cellular environment is known to impact strain morphology. And, asyn aggregate pathology can propagate trans-synaptically along the brain-body axis, affecting multiple organs and propagating through multiple cell types. Here, we present our hypothesis that the changing cellular environments, an asyn seed may encounter during its brain-to-body or body-to-brain propagation, may influence the structure and thereby the function of the aggregate strains developing within the different cells. Additionally, we aim to review strain characteristics of the different synucleinopathies in clinical and preclinical studies. Future preclinical animal models of synucleinopathies should investigate if asyn strain morphology is altered during brain-to-body and body-to-brain spreading using these seeding amplification and conformation-specific assays. Such findings would greatly deepen our understanding of synucleinopathies and the potential link between strain and phenotypic variability, which may enable specific diagnosis of different synucleinopathies in the prodromal phase, creating a large therapeutic window with potential future applications in clinical trials and personalized therapeutics.

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Section: Alpha-synuclein and Strain Variabilitymentioning

confidence: 99%

Section: Luminescent Conjugated Oligothiophenes To Identify Different...mentioning

confidence: 99%

Section: Luminescent Conjugated Oligothiophenes To Identify Different...mentioning

confidence: 99%

See 1 more Smart Citation

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

Just

Gram

Theologidis

et al. 2022

Front. Aging Neurosci.

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“…To make a comparative conformational analysis of Aβ1–42 fibrils formed in the absence and presence of chaperones, we performed hyperspectral fluorescence microscopy analysis of fibrils incubated without ThT for 48 h and thereafter co-stained with the conformation sensitive luminescent conjugated oligothiophenes (LCOs) qFTAA and hFTAA ( Nyström et al, 2013 ; Rasmussen et al, 2017 ; Liu et al, 2021 ). Aβ1–42 fibrils formed in vitro are usually dominated by hFTAA fluorescence as is displayed by low ratio values in the ratio plot of qFTAA/hFTAA fluorescence ( Figure 4B ).…”

Section: Resultsmentioning

confidence: 99%

“…One of the key points in protein aggregation diseases is the multitude of structures, known as polymorphism, that appear because of the plasticity of misfolded proteins. Hence, we hypothesized that this is an important mechanism for disease phenotype and refer to these diseases in plural, e.g., Alzheimer’s diseases ( Rasmussen et al, 2017 ; Liu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils

2022

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Neurodegenerative diseases (NDs) are associated with accumulated misfolded proteins (MPs). MPs oligomerize and form multiple forms of amyloid fibril polymorphs that dictate fibril propagation and cellular dysfunction. Protein misfolding processes that impair protein homeostasis are implicated in onset and progression of NDs. A wide variety of molecular chaperones safeguard the cell from MP accumulation. A rather overlooked molecular chaperone is HSP10, known as a co-chaperone for HSP60. Due to the ubiquitous presence in human tissues and protein overabundance compared with HSP60, we studied how HSP10 alone influences fibril formation in vitro of Alzheimer’s disease-associated Aβ1–42. At sub-stoichiometric concentrations, eukaryotic HSP10s (human and Drosophila) significantly influenced the fibril formation process and the fibril structure of Aβ1–42, more so than the prokaryotic HSP10 GroES. Similar effects were observed for prion disease-associated prion protein HuPrP90–231. Paradoxically, for a chaperone, low concentrations of HSP10 appeared to promote fibril nucleation by shortened lag-phases, which were chaperone and substrate dependent. Higher concentrations of chaperone while still sub-stoichiometric extended the nucleation and/or the elongation phase. We hypothesized that HSP10 by means of its seven mobile loops provides the chaperone with high avidity binding to amyloid fibril ends. The preserved sequence of the edge of the mobile loop GGIM(V)L (29–33 human numbering) normally dock to the HSP60 apical domain. Interestingly, this segment shows sequence similarity to amyloidogenic core segments of Aβ1–42, GGVVI (37–41), and HuPrP90-231 GGYML (126–130) likely allowing efficient competitive binding to fibrillar conformations of these MPs. Our results propose that HSP10 can function as an important molecular chaperone in human proteostasis in NDs.

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Genome‐wide association studies identify novel loci in rapidly progressive Alzheimer's disease

Wang,

Lynn,

Miskimen

et al. 2024

Alzheimer's & Dementia

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INTRODUCTIONRecent data suggest that distinct prion‐like amyloid beta and tau strains are associated with rapidly progressive Alzheimer's disease (rpAD). The role of genetic factors in rpAD is largely unknown.METHODSPreviously known AD risk loci were examined in rpAD cases. Genome‐wide association studies (GWAS) were performed to identify variants that influence rpAD.RESULTSWe identified 115 pathology‐confirmed rpAD cases and 193 clinical rpAD cases, 80% and 69% were of non‐Hispanic European ancestry. Compared to the clinical cohort, pathology‐confirmed rpAD had higher frequencies of apolipoprotein E (APOE) ε4 and rare missense variants in AD risk genes. A novel genome‐wide significant locus (P < 5×10−8) was observed for clinical rpAD on chromosome 21 (rs2832546); 102 loci showed suggestive associations with pathology‐confirmed rpAD (P < 1×10−5).DISCUSSIONrpAD constitutes an extreme subtype of AD with distinct features. GWAS found previously known and novel loci associated with rpAD.Highlights Rapidly progressive Alzheimer's disease (rpAD) was defined with different criteria. Whole genome sequencing identified rare missense variants in rpAD. Novel variants were identified for clinical rpAD on chromosome 21.

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Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease

Cited by 29 publications

References 72 publications

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

Alpha-Synuclein Strain Variability in Body-First and Brain-First Synucleinopathies

HSP10 as a Chaperone for Neurodegenerative Amyloid Fibrils

Genome‐wide association studies identify novel loci in rapidly progressive Alzheimer's disease

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