Significant Overlap of α-Synuclein, Amyloid-β, and Phospho-Tau Pathologies in Neuropathological Diagnosis of Lewy-related Pathology: Evidence from China Human Brain Bank

2021 ◽  
Vol 80 (1) ◽  
pp. 447-458 ◽  
Author(s):  
Cong Cong ◽  
Wanying Zhang ◽  
Xiaojing Qian ◽  
Wenying Qiu ◽  
Chao Ma
Keyword(s):  
Human Brain ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Brain Bank ◽  
Predominant Type ◽  
Neuropathological Diagnosis ◽  
Postmortem Brains ◽  
The Common ◽  
High Level ◽  
Human Brains

Background: Lewy-related pathology (LRP), primarily comprised of α-synuclein, is a typical neuropathological change that has been identified in many neurodegenerative disorders such as Parkinson’s disease (PD), PD with dementia, and dementia with Lewy bodies. Objective: To investigate the distribution of LRP in the China Human Brain Bank, the co-occurrence of neuropathologic features of Alzheimer’s disease (AD) in LRP cases, and LRP-related cognitive dysfunction. Methods: LRP neuropathological diagnosis was performed in 180 postmortem brains. AD neuropathological diagnosis was then performed in the 21 neuropathologically-diagnosed LRP cases. Antemortem cognitive functioning evaluation (Everyday Cognitive, ECog) was assessed for brain donors by the immediate kin of the donor within 24 hours after death. Results: 12% (21 in 180) postmortem brains were neuropathologically diagnosed as LRP cases. 86% (18 in 21) aged above 80, 81% (17 in 21) LRP cases combined with AD neuropathology, and 62% (13 in 21) combined with both the intermediate or high-level amyloid-β and phospho-tau pathologies. ECog scores showed significant differences between the groups of LRP brainstem-predominant type and LRP diffuse neocortical type, and between groups of AD and the combined LRP (diffuse neocortical type)-AD. Conclusion: The overlap of neocortical α-synuclein, amyloid-β, phospho-tau, and neuritic plaques in LRP suggested the potential interplay among the common characteristics of proteinopathies in the late stage of neuropathological development of LRP in human brains. The anatomic progression of LRP, the process of α-synuclein spreading from the brainstem to limbic and neocortical regions, might aggravate the deterioration of cognitive function in addition to that effect of AD.

The Correlations between Postmortem Brain Pathologies and Cognitive Dysfunction in Aging and Alzheimer's Disease

2018 ◽  
Vol 15 (5) ◽  
pp. 462-473 ◽  
Author(s):  
Wen-Ying Qiu ◽  
Qian Yang ◽  
Wanying Zhang ◽  
Naili Wang ◽  
Di Zhang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Brain ◽  
Amyloid Β ◽  
Cognitive Status ◽  
Postmortem Brain ◽  
Braak Stage ◽  
Brain Bank ◽  
General Linear Multivariate Model ◽  
Human Brains

Background: The pathological diagnostic criteria for Alzheimer's disease (AD) updated by the National Institute on Aging-Alzheimer's Association (NIA-AA) in 2012 has been widely adopted, but the clinicopathological relevance remained obscure in Chinese population. Objective: This study aims to investigate the correlations between the antemortem clinical cognitive performances and the postmortem neuropathological changes in the aging and AD brains collected in a human brain bank in China. Method: A total of 52 human brains with antemortem cognitive status information [Everyday Cognition (ECog)] were collected through the willed donation program by CAMS/PUMC Human Brain Bank. Pathological changes were evaluated with the “ABC” score following the guidelines of NIA-AA. The clinicopathological relationship was analyzed with correlation analysis and general linear multivariate model. Results: The general ABC score has a significant correlation with global ECog score (r=0.37, p=0.014) and most of ECog domains. The CERAD score of neuritic plaques (C score) has a significant correlation with global ECog score (r=0.40, p=0.007) and the majority of ECog domains, such as memory (r=0.50, p=0.001), language (r=0.45, p=0.002), visuospatial functions (r=0.31, p=0.040), planning (r=0.35, p=0.021) and organization (r=0.39, p=0.010). The Braak stage of neurofibrillary tangles (NFTs) (B score) has a moderate correlation with memory (r=0.32, p=0.035). The Thal phases of amyloid-β (Aβ) deposits (A score) present no significant correlation with any of ECog domains. Conclusion: In this study, we verified the correlation of postmortem C and B scores, but not the A score with cognition performance in a collection of samples from the Chinese human brain bank.

scholarly journals Copper(II)-induced self-oligomerization of α-synuclein

1999 ◽  
Vol 340 (3) ◽  
pp. 821-828 ◽  
Author(s):  
Seung R. PAIK ◽  
Hyun-Ju SHIN ◽  
Ju-Hyun LEE ◽  
Chung-Soon CHANG ◽  
Jongsun KIM
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Metal Ion ◽  
Senile Plaques ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Coupling Reagents ◽  
C Terminus ◽  
Nucleation Centre ◽  
The Common

α-Synuclein is a component of the abnormal protein depositions in senile plaques and Lewy bodies of Alzheimer's disease (AD) and Parkinson's disease respectively. The protein was suggested to provide a possible nucleation centre for plaque formation in AD via selective interaction with amyloid β/A4 protein (Aβ). We have shown previously that α-synuclein has experienced self-oligomerization when Aβ25-35 was present in an orientation-specific manner in the sequence. Here we examine this biochemically specific self-oligomerization with the use of various metals. Strikingly, copper(II) was the most effective metal ion affecting α-synuclein to form self-oligomers in the presence of coupling reagents such as dicyclohexylcarbodi-imide or N-(ethoxycarbonyl)-2-ethoxy-1,2-dihydroquinoline. The size distribution of the oligomers indicated that monomeric α-synuclein was oligomerized sequentially. The copper-induced oligomerization was shown to be suppressed as the acidic C-terminus of α-synuclein was truncated by treatment with endoproteinase Asp-N. In contrast, the Aβ25-35-induced oligomerizations of the intact and truncated forms of α-synuclein were not affected. This clearly indicated that the copper-induced oligomerization was dependent on the acidic C-terminal region and that its underlying biochemical mechanism was distinct from that of the Aβ25-35-induced oligomerization. Although the physiological or pathological relevance of the oligomerization remains currently elusive, the common outcome of α-synuclein on treatment with copper or Aβ25-35 might be useful in understanding neurodegenerative disorders in molecular terms. In addition, abnormal copper homoeostasis could be considered as one of the risk factors for the development of disorders such as AD or Parkinson's disease.

Cryo-EM structures of amyloid-β 42 filaments from human brains

Science ◽  
2022 ◽  
Vol 375 (6577) ◽  
pp. 167-172
Author(s):  
Yang Yang ◽  
Diana Arseni ◽  
Wenjuan Zhang ◽  
Melissa Huang ◽  
Sofia Lövestam ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Animal Models ◽  
Human Brain ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Cryo Electron Microscopy ◽  
Specificity And Sensitivity ◽  
Human Brains ◽  
The Brain

Hi-res view of human Aβ42 filaments Alzheimer’s disease is characterized by a loss of memory and other cognitive functions and the filamentous assembly of Aβ and tau in the brain. The assembly of Aβ peptides into filaments that end at residue 42 is a central event. Yang et al . used electron cryo–electron microscopy to determine the structures of Aβ42 filaments from human brain (see the Perspective by Willem and Fändrich). They identified two types of related S-shaped filaments, each consisting of two identical protofilaments. These structures will inform the development of better in vitro and animal models, inhibitors of Aβ42 assembly, and imaging agents with increased specificity and sensitivity. —SMH

scholarly journals APOE4 exacerbates α-synuclein pathology and related toxicity independent of amyloid

2020 ◽  
Vol 12 (529) ◽  
pp. eaay1809 ◽  
Author(s):  
Na Zhao ◽  
Olivia N. Attrebi ◽  
Yingxue Ren ◽  
Wenhui Qiao ◽  
Berkiye Sonustun ◽  
...  
Keyword(s):  
Risk Factor ◽  
Genetic Risk ◽  
Late Onset ◽  
Lewy Bodies ◽  
Amyloid Β ◽  
Lewy Body Dementia ◽  
Genetic Risk Factor ◽  
Adeno Associated Virus ◽  
Postmortem Brains ◽  
Ε4 Allele

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease mainly by driving amyloid-β pathology. Recently, APOE4 has also been found to be a genetic risk factor for Lewy body dementia (LBD), which includes dementia with Lewy bodies and Parkinson’s disease dementia. How APOE4 drives risk of LBD and whether it has a direct effect on α-synuclein pathology are not clear. Here, we generated a mouse model of synucleinopathy using an adeno-associated virus gene delivery of α-synuclein in human APOE-targeted replacement mice expressing APOE2, APOE3, or APOE4. We found that APOE4, but not APOE2 or APOE3, increased α-synuclein pathology, impaired behavioral performances, worsened neuronal and synaptic loss, and increased astrogliosis at 9 months of age. Transcriptomic profiling in APOE4-expressing α-synuclein mice highlighted altered lipid and energy metabolism and synapse-related pathways. We also observed an effect of APOE4 on α-synuclein pathology in human postmortem brains with LBD and minimal amyloid pathology. Our data demonstrate a pathogenic role of APOE4 in exacerbating α-synuclein pathology independent of amyloid, providing mechanistic insights into how APOE4 increases the risk of LBD.

Negotiations over Accounting Issues: The Congruency of Audit Partner and Chief Financial Officer Recalls

2005 ◽  
Vol 24 (s-1) ◽  
pp. 171-193 ◽  
Author(s):  
Michael Gibbins ◽  
Susan A. McCracken ◽  
Steven E. Salterio
Keyword(s):  
Negotiation Process ◽  
Chief Financial Officers ◽  
Chief Financial Officer ◽  
Relative Importance ◽  
Common Elements ◽  
Contextual Features ◽  
Large Numbers ◽  
The Common ◽  
High Level ◽  
Two Sides

Much of what takes place in auditor-client management negotiations occurs in unobservable settings and normally does not result in publicly available archival records. Recent research has increasingly attempted to probe issues relating to accounting negotiations in part due to recent events in the financial world. In this paper, we compare recalls from the two sides of such negotiations, audit partners, and chief financial officers (CFOs), collected in two field questionnaires. We examine the congruency of the auditors' and the CFOs' negotiation recalls for all negotiation elements and features that were common across the two questionnaires (detailed analyses of the questionnaires are reported elsewhere). The results show largely congruent recall: only limited divergences in recall of common elements and features. Specifically, we show a high level of congruency across CFOs and audit partners in the type of issues negotiated, parties involved in resolving the issue, and the elements making up the negotiation process, including agreement on the relative importance of various common accounting contextual features. The analysis of the common accounting contextual features suggests that certain contextual features are consistently important across large numbers of negotiations, whether viewed from the audit partner's or the CFO's perspective, and hence may warrant future study. Finally, the comparative analysis allows us to identify certain common elements and contextual features that may influence both audit partners and CFOs to consider the accounting negotiation setting as mainly distributive (win-lose).

Caged-electron States and Split-electron States in Endohedral Alkali C60

2021 ◽  
Author(s):  
yifan yang ◽  
Lorenz S Cederbaum
Keyword(s):  
State Of The Art ◽  
Electronic States ◽  
Electron States ◽  
The Common ◽  
High Level

The low-lying electronic states of neutral X@C60(X=Li, Na, K, Rb) have been computed and analyzed by employing state-of-the-art high level many-electron methods. Apart from the common charge-separated states, well known...

scholarly journals The role of cultural practices in the emergence of modern human intelligence

2008 ◽  
Vol 363 (1499) ◽  
pp. 2011-2019 ◽  
Author(s):  
Edwin Hutchins
Keyword(s):  
Embodied Cognition ◽  
Cognitive Processes ◽  
Human Activities ◽  
Cultural Practices ◽  
Modern Human ◽  
Human Intelligence ◽  
Symbolic Representations ◽  
High Level ◽  
Human Brains

Innate cognitive capacities are orchestrated by cultural practices to produce high-level cognitive processes. In human activities, examples of this phenomenon range from everyday inferences about space and time to the most sophisticated reasoning in scientific laboratories. A case is examined in which chimpanzees enter into cultural practices with humans (in experiments) in ways that appear to enable them to engage in symbol-mediated thought. Combining the cultural practices perspective with the theories of embodied cognition and enactment suggests that the chimpanzees' behaviour is actually mediated by non-symbolic representations. The possibility that non-human primates can engage in cultural practices that give them the appearance of symbol-mediated thought opens new avenues for thinking about the coevolution of human culture and human brains.

scholarly journals P-Glycoprotein and Breast Cancer Resistance Protein Restrict Apical-to-Basolateral Permeability of Human Brain Endothelium to Amyloid-β

2009 ◽  
Vol 29 (6) ◽  
pp. 1079-1083 ◽  
Author(s):  
Leon M Tai ◽  
A Jane Loughlin ◽  
David K Male ◽  
Ignacio A Romero
Keyword(s):  
Breast Cancer ◽  
Human Brain ◽  
Breast Cancer Resistance Protein ◽  
Amyloid Β ◽  
Cancer Resistance ◽  
Glycoprotein P ◽  
P Glycoprotein ◽  
Resistance Protein ◽  
The Brain

The clearance of amyloid beta (Aβ) from the brain represents a novel therapeutic target for Alzheimer's disease. Conflicting data exist regarding the contribution of adenosine triphosphatebinding cassette transporters to the clearance of Aβ through the blood-brain barrier. Therefore, we investigated whether Aβ could be a substrate for P-glycoprotein (P-gp) and/or for breast cancer resistance protein (BCRP) using a human brain endothelial cell line, hCMEC/D3. Inhibition of P-gp and BCRP increased apical-to-basolateral, but not basolateral-to-apical, permeability of hCMEC/D3 cells to 125l Aβ 1–40. Our in vitro data suggest that P-gp and BCRP might act to prevent the blood-borne Aβ 1–40 from entering the brain.

scholarly journals Robust α-synuclein pathology in select brainstem neuronal populations is a potential instigator of multiple system atrophy

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Ethan W. Hass ◽  
Zachary A. Sorrentino ◽  
Grace M. Lloyd ◽  
Nikolaus R. McFarland ◽  
Stefan Prokop ◽  
...  
Keyword(s):  
Multiple System Atrophy ◽  
Lewy Bodies ◽  
Biochemical Properties ◽  
Detection Methods ◽  
Inferior Olivary Nucleus ◽  
Cytoplasmic Inclusions ◽  
Neuronal Populations ◽  
Carboxy Terminal Region ◽  
High Level ◽  
Carboxy Terminal

AbstractMultiple system atrophy (MSA) is an insidious middle age-onset neurodegenerative disease that clinically presents with variable degrees of parkinsonism and cerebellar ataxia. The pathological hallmark of MSA is the progressive accumulation of glial cytoplasmic inclusions (GCIs) in oligodendrocytes that are comprised of α-synuclein (αSyn) aberrantly polymerized into fibrils. Experimentally, MSA brain samples display a high level of seeding activity to induce further αSyn aggregation by a prion-like conformational mechanism. Paradoxically, αSyn is predominantly a neuronal brain protein, with only marginal levels expressed in normal or diseased oligodendrocytes, and αSyn inclusions in other neurodegenerative diseases, including Parkinson’s disease and Dementia with Lewy bodies, are primarily found in neurons. Although GCIs are the hallmark of MSA, using a series of new monoclonal antibodies targeting the carboxy-terminal region of αSyn, we demonstrate that neuronal αSyn pathology in MSA patient brains is remarkably abundant in the pontine nuclei and medullary inferior olivary nucleus. This neuronal αSyn pathology has distinct histological properties compared to GCIs, which allows it to remain concealed to many routine detection methods associated with altered biochemical properties of the carboxy-terminal domain of αSyn. We propose that these previously underappreciated sources of aberrant αSyn could serve as a pool of αSyn prion seeds that can initiate and continue to drive the pathogenesis of MSA.

Ba-, Si- and vacancy-rich phlogopites from the talc-bearing sulfide ore deposit of La Creuse, Beaujolais, France

2018 ◽  
Vol 82 (5) ◽  
pp. 1187-1210
Author(s):  
Marie-Lola Pascal ◽  
Michel Fonteilles ◽  
Véronique Tournis ◽  
Benoît Baptiste ◽  
Jean-Louis Robert ◽  
...  
Keyword(s):  
Goodness Of Fit ◽  
Monoclinic Space Group ◽  
Excess Charge ◽  
Formula Unit ◽  
X Ray Diffraction ◽  
Ore Deposit ◽  
Sulfide Ore ◽  
The Common ◽  
The Stability ◽  
High Level

ABSTRACTBa-rich and Si-rich phlogopites occur in the talc-bearing rocks of the La Creuse sulfide ore deposit in Beaujolais, France. They form a group of compositions completely separated from the common Al-rich phlogopites that occur in the surrounding talc-free metasiltites and metarhyolites, with higher Ba and Mg and lower Al contents. The Ba-rich phlogopites have a relatively narrow compositional range (0.24 to 0.80 Ba per formula unit, for 44 valencies) with high and constant Si (5.8 atoms per formula unit, apfu) and Mg + Fe (5.6 apfu), probably buffered by the presence of talc. Compared to low-Al phlogopites from talc-free rocks, the excess charge introduced by the BaK–1 substitution is compensated by interlayer vacancies. Such a high level of interlayer vacancy (0.56 pfu), related to the talc-producing metasomatic conditions, is essential for the stability of this special group of Ba-rich and Si-rich phlogopites.Single crystal X-ray diffraction analyses were performed. Ba-rich and Si-rich phlogopite is monoclinic, space group C2/m, (R = 5.31%) with a = 5.3185(5), b = 9.2136(9), c = 10.1349(11) Å and β = 100.131(11)°. The occupancies of Mg/Fe and K/Ba were refined exploring different vacancies. The solutions giving the best R factor (4.77%) and goodness-of-fit (1.06) are obtained with 15% < vacancy < 40% at the interlayer site.

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