scholarly journals Structural progression of amyloid-β Arctic mutant aggregation in cells revealed by multiparametric imaging

2018 ◽  
Vol 294 (5) ◽  
pp. 1478-1487 ◽  
Author(s):  
Meng Lu ◽  
Neil Williamson ◽  
Ajay Mishra ◽  
Claire H. Michel ◽  
Clemens F. Kaminski ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Arctic ◽  
Structural Basis ◽  
Fluorescence Lifetime Imaging ◽  
Intracellular Degradation ◽  
Mutant Variant ◽  
Structural Progression ◽  
Β Amyloid

The 42-amino-acid β-amyloid (Aβ42) is a critical causative agent in the pathology of Alzheimer's disease. The hereditary Arctic mutation of Aβ42 (E22G) leads to increased intracellular accumulation of β-amyloid in early-onset Alzheimer's disease. However, it remains largely unknown how the Arctic mutant variant leads to aggressive protein aggregation and increased intracellular toxicity. Here, we constructed stable cell lines expressing fluorescent-tagged wildtype (WT) and E22G Aβ42 to study the aggregation kinetics of the Arctic Aβ42 mutant peptide and its heterogeneous structural forms. Arctic-mutant peptides assemble and form fibrils at a much faster rate than WT peptides. We identified five categories of intracellular aggregate—oligomers, single fibrils, fibril bundles, clusters, and aggresomes—that underline the heterogeneity of these Aβ42 aggregates and represent the progression of Aβ42 aggregation within the cell. Fluorescence-lifetime imaging (FLIM) and 3D structural illumination microscopy (SIM) showed that all aggregate species displayed highly compact structures with strong affinity between individual fibrils. We also found that aggregates formed by Arctic mutant Aβ42 were more resistant to intracellular degradation than their WT counterparts. Our findings uncover the structural basis of the progression of Arctic mutant Aβ42 aggregation in the cell.

scholarly journals Three-dimensional analysis of synaptic organization in the hippocampal CA1 field in Alzheimer’s disease

Brain ◽  
2020 ◽  
Author(s):  
Marta Montero-Crespo ◽  
Marta Domínguez-Álvaro ◽  
Lidia Alonso-Nanclares ◽  
Javier DeFelipe ◽  
Lidia Blazquez-Llorca
Keyword(s):  
Electron Microscopy ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cortical Atrophy ◽  
Structural Basis ◽  
Synaptic Organization ◽  
Synaptic Density ◽  
Early Stages ◽  
Late Stages

Abstract Alzheimer’s disease is the most common form of dementia, characterized by a persistent and progressive impairment of cognitive functions. Alzheimer’s disease is typically associated with extracellular deposits of amyloid-β peptide and accumulation of abnormally phosphorylated tau protein inside neurons (amyloid-β and neurofibrillary pathologies). It has been proposed that these pathologies cause neuronal degeneration and synaptic alterations, which are thought to constitute the major neurobiological basis of cognitive dysfunction in Alzheimer’s disease. The hippocampal formation is especially vulnerable in the early stages of Alzheimer’s disease. However, the vast majority of electron microscopy studies have been performed in animal models. In the present study, we performed an extensive 3D study of the neuropil to investigate the synaptic organization in the stratum pyramidale and radiatum in the CA1 field of Alzheimer’s disease cases with different stages of the disease, using focused ion beam/scanning electron microscopy (FIB/SEM). In cases with early stages of Alzheimer’s disease, the synapse morphology looks normal and we observed no significant differences between control and Alzheimer’s disease cases regarding the synaptic density, the ratio of excitatory and inhibitory synapses, or the spatial distribution of synapses. However, differences in the distribution of postsynaptic targets and synaptic shapes were found. Furthermore, a lower proportion of larger excitatory synapses in both strata were found in Alzheimer’s disease cases. Individuals in late stages of the disease suffered the most severe synaptic alterations, including a decrease in synaptic density and morphological alterations of the remaining synapses. Since Alzheimer’s disease cases show cortical atrophy, our data indicate a reduction in the total number (but not the density) of synapses at early stages of the disease, with this reduction being much more accentuated in subjects with late stages of Alzheimer’s disease. The observed synaptic alterations may represent a structural basis for the progressive learning and memory dysfunctions seen in Alzheimer’s disease cases.

scholarly journals Ingredients in Zijuan Pu’er Tea Extract Alleviate β-Amyloid Peptide Toxicity in a Caenorhabditis elegans Model of Alzheimer’s Disease Likely through DAF-16

Molecules ◽  
2019 ◽  
Vol 24 (4) ◽  
pp. 729 ◽  
Author(s):  
Fangzhou Du ◽  
Lin Zhou ◽  
Yan Jiao ◽  
Shuju Bai ◽  
Lu Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Caenorhabditis Elegans ◽  
Protective Effect ◽  
Nuclear Translocation ◽  
Amyloid Β ◽  
Amyloid Peptide ◽  
C Elegans ◽  
Β Amyloid

Amyloid-β, one of the hallmarks of Alzheimer’s disease (AD), is toxic to neurons and can also cause brain cell death. Oxidative stress is known to play an important role in AD, and there is strong evidence that oxidative stress is associated with amyloid-β. In the present study we report the protective effect of Zijuan Pu’er tea water extract (ZTWE) and the mixture of main ingredients (+)-catechins, caffeine and procyanidin (MCCP) in ZTWE on β-amyloid-induced toxicity in transgenic Caenorhabditis elegans (C. elegans) CL4176 expressing the human Aβ1–42 gene. ZTWE, (+)-catechins, caffeine, procyanidin and MCCP delayed the β-amyloid-induced paralysis to different degrees. The MCCP treatment did not affect the transcript abundance of amyloid-β transgene (amy-1); however, Thioflavin T staining showed a significant decrease in Aβ accumulation compared to untreated worms. Further research using transgenic worms found that MCCP promoted the translocation of DAF-16 from cytoplasm to nucleus and increased the expression of superoxide dismutase 3 (SOD-3). In addition, MCCP decreased the reactive oxygen species (ROS) content and increased the SOD activity in CL4176 worms. In conclusion, the results suggested that MCCP had a significant protective effect on β-amyloid-induced toxicity in C. elegans by reducing β-amyloid aggregation and inducing DAF-16 nuclear translocation that could activate the downstream signal pathway and enhance resistance to oxidative stress.

scholarly journals The HHQK Domain of β-Amyloid Provides a Structural Basis for the Immunopathology of Alzheimer’s Disease

1998 ◽  
Vol 273 (45) ◽  
pp. 29719-29726 ◽  
Author(s):  
Dana Giulian ◽  
Lanny J. Haverkamp ◽  
Jiahan Yu ◽  
William Karshin ◽  
Donald Tom ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Structural Basis ◽  
Β Amyloid

scholarly journals Biflavonoid-Induced Disruption of Hydrogen Bonds Leads to Amyloid-b Disaggregation

2021 ◽  
Vol 22 (6) ◽  
pp. 2888
Author(s):  
Peter K. Windsor ◽  
Stephen P. Plassmeyer ◽  
Dominic S. Mattock ◽  
Jonathan C. Bradfield ◽  
Erika Y. Choi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Hydrogen Bond ◽  
Amyloid Β ◽  
Structural Basis ◽  
Hydroxyl Groups ◽  
Dependent Manner ◽  
Dynamic Simulations ◽  
Hydrogen Bond Formation ◽  
Aβ Fibrils

Deposition of amyloid β (Aβ) fibrils in the brain is a key pathologic hallmark of Alzheimer’s disease. A class of polyphenolic biflavonoids is known to have anti-amyloidogenic effects by inhibiting aggregation of Aβ and promoting disaggregation of Aβ fibrils. In the present study, we further sought to investigate the structural basis of the Aβ disaggregating activity of biflavonoids and their interactions at the atomic level. A thioflavin T (ThT) fluorescence assay revealed that amentoflavone-type biflavonoids promote disaggregation of Aβ fibrils with varying potency due to specific structural differences. The computational analysis herein provides the first atomistic details for the mechanism of Aβ disaggregation by biflavonoids. Molecular docking analysis showed that biflavonoids preferentially bind to the aromatic-rich, partially ordered N-termini of Aβ fibril via the p–p interactions. Moreover, docking scores correlate well with the ThT EC50 values. Molecular dynamic simulations revealed that biflavonoids decrease the content of β-sheet in Aβ fibril in a structure-dependent manner. Hydrogen bond analysis further supported that the substitution of hydroxyl groups capable of hydrogen bond formation at two positions on the biflavonoid scaffold leads to significantly disaggregation of Aβ fibrils. Taken together, our data indicate that biflavonoids promote disaggregation of Aβ fibrils due to their ability to disrupt the fibril structure, suggesting biflavonoids as a lead class of compounds to develop a therapeutic agent for Alzheimer’s disease.

scholarly journals Alzheimer’s Disease: A Molecular View of β-Amyloid Induced Morbific Events

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1126
Author(s):  
Rajmohamed Mohamed Asik ◽  
Natarajan Suganthy ◽  
Mohamed Asik Aarifa ◽  
Arvind Kumar ◽  
Krisztián Szigeti ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Status ◽  
Amyloid Β ◽  
Telomerase Activity ◽  
Unfolded Protein ◽  
Cell Compartments ◽  
Β Amyloid ◽  
Protein Response ◽  
Inflammatory Molecules

Amyloid-β (Aβ) is a dynamic peptide of Alzheimer’s disease (AD) which accelerates the disease progression. At the cell membrane and cell compartments, the amyloid precursor protein (APP) undergoes amyloidogenic cleavage by β- and γ-secretases and engenders the Aβ. In addition, externally produced Aβ gets inside the cells by receptors mediated internalization. An elevated amount of Aβ yields spontaneous aggregation which causes organelles impairment. Aβ stimulates the hyperphosphorylation of tau protein via acceleration by several kinases. Aβ travels to the mitochondria and interacts with its functional complexes, which impairs the mitochondrial function leading to the activation of apoptotic signaling cascade. Aβ disrupts the Ca2+ and protein homeostasis of the endoplasmic reticulum (ER) and Golgi complex (GC) that promotes the organelle stress and inhibits its stress recovery machinery such as unfolded protein response (UPR) and ER-associated degradation (ERAD). At lysosome, Aβ precedes autophagy dysfunction upon interacting with autophagy molecules. Interestingly, Aβ act as a transcription regulator as well as inhibits telomerase activity. Both Aβ and p-tau interaction with neuronal and glial receptors elevate the inflammatory molecules and persuade inflammation. Here, we have expounded the Aβ mediated events in the cells and its cosmopolitan role on neurodegeneration, and the current clinical status of anti-amyloid therapy.

scholarly journals PGRN Alleviates Cerebral Amyloid-β Burden and Cognitive Impairments via Mediating Neuroinflammation

2020 ◽  
Author(s):  
Wei Xu ◽  
Chen-Chen Tan ◽  
Xi-Peng Cao ◽  
Jin-Tai Yu ◽  
Lan Tan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairments ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Mediation Effects ◽  
Mediation Analyses ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Tgf Β1

Abstract Background: Both progranulin (PGRN) and neuroinflammatory activities increased over the course of Alzheimer’s disease (AD). In this study, we set out to determine if cerebrospinal fluid (CSF) PGRN could be a marker of neuroinflammation, and if so, how it contributed to AD pathogenesis and cognitive impairments. Methods: A total of 965 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were grouped within the framework of A-T-N biomarker profile and clinical stage. Causal mediation analyses with 10,000 bootstrapped iterations were conducted to explore the mediation effects of neuroinflammatory markers on the associations of PGRN with amyloid burden indicated by CSF β-amyloid (Aβ) levels. The longitudinal influences of PGRN on cognition were tested. Results: Increases of CSF PGRN and multiple neuroinflammatory markers (sTNFR1, sTNFR2, TGF-β1, VCAM1, and ICAM1) were associated with tau-related neurodegeneration, but not with Aβ pathology. PGRN was positively linked with these neuroinflammatory markers only in the presence of tau pathologies (TN+). In TN+ profile, PGRN was associated with higher CSF Aβ42 via mediating neuroinflammatory markers and could also predict slower cognitive decline. The abovementioned associations became non-significant in TN- profile. Conclusions: PGRN could protect against Aβ pathology and cognitive impairments via modulating neuroinflammation that occurs with neuronal injuries.

scholarly journals Synergistic effects of hypertension and aging on cognitive function and hippocampal expression of genes involved in β-amyloid generation and Alzheimer's disease

2013 ◽  
Vol 305 (8) ◽  
pp. H1120-H1130 ◽  
Author(s):  
Anna Csiszar ◽  
Zsuzsanna Tucsek ◽  
Peter Toth ◽  
Danuta Sosnowska ◽  
Tripti Gautam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Protein Binding ◽  
Synergistic Effects ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Precursor Protein ◽  
Expression Of Genes ◽  
Β Amyloid

Strong epidemiological and experimental evidence indicate that hypertension in the elderly predisposes to the development of Alzheimer's disease (AD), but the underlying mechanisms remain elusive. The present study was designed to characterize the additive/synergistic effects of hypertension and aging on the expression of genes involved in β-amyloid generation and AD in the hippocampus, an area of brain contributing to higher cognitive function, which is significantly affected by AD both in humans and in mouse models of the disease. To achieve that goal, we induced hypertension in young (3 mo) and aged (24 mo) C57BL/6 mice by chronic (4 wk) infusion of angiotensin II and assessed changes in hippocampal mRNA expression of genes involved in amyloid precursor protein (APP)-dependent signaling, APP cleavage, Aβ processing and Aβ-degradation, synaptic function, dysregulation of microtubule-associated τ protein, and apolipoprotein-E signaling. Aged hypertensive mice exhibited spatial memory impairments in the Y-maze and impaired performance in the novel object recognition assay. Surprisingly, hypertension in aging did not increase the expression of APP, β- and γ-secretases, or genes involved in tauopathy. These genes are all involved in the early onset form of AD. Yet, hypertension in aging was associated with changes in hippocampal expression of APP binding proteins, e.g., [Mint3/amyloid β A4 precursor protein-binding family A member 3 (APBA3), Fe65/amyloid β A4 precursor protein-binding family B member 1 (APBB1)], amyloid β (A4) precursor-like protein 1 (APLP1), muscarinic M1 receptor, and serum amyloid P component, all of which may have a role in the pathogenesis of late-onset AD. The hippocampal gene expression signature observed in aged hypertensive mice in the present study provides important clues for subsequent studies to elucidate the mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of AD.

scholarly journals Target-driven supramolecular self-assembly for selective amyloid-β photooxygenation against Alzheimer's disease

2020 ◽  
Vol 11 (40) ◽  
pp. 11003-11008
Author(s):  
Zhenqi Liu ◽  
Mengmeng Ma ◽  
Dongqin Yu ◽  
Jinsong Ren ◽  
Xiaogang Qu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Photodynamic Therapy ◽  
Self Assembly ◽  
Amyloid Β ◽  
Aβ Aggregation ◽  
Amyloid Aβ ◽  
Β Amyloid

Photo-oxygenation of β-amyloid (Aβ) has been considered an efficient way to inhibit Aβ aggregation in Alzheimer's disease (AD). We present the first example of Aβ-responsive photodynamic therapy to treatment of AD by using PKNPs self-assemblies.

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