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.

Astrocyte Reactivity in Alzheimer’s Disease: Therapeutic Opportunities to Promote Repair

2021 ◽  
Vol 18 ◽  
Author(s):  
Nazanin Mirzaei ◽  
Nicola Davis ◽  
Tsz Wing Chau ◽  
Magdalena Sastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Mouse Models ◽  
Neurodegenerative Disorders ◽  
Amyloid Β ◽  
Neuroprotective Effects ◽  
Synaptic Density ◽  
Inflammatory Profile

: Astrocytes are fast climbing the ladder of importance in neurodegenerative disorders, particularly in Alzheimer’s disease (AD), with the prominent presence of reactive astrocytes sur- rounding amyloid β- plaques, together with activated microglia. Reactive astrogliosis, implying morphological and molecular transformations in astrocytes, seems to precede neurodegeneration, suggesting a role in the development of the disease. Single-cell transcriptomics has recently demon- strated that astrocytes from AD brains are different from “normal” healthy astrocytes, showing dys- regulations in areas such as neurotransmitter recycling, including glutamate and GABA, and im- paired homeostatic functions. However, recent data suggest that the ablation of astrocytes in mouse models of amyloidosis results in an increase in amyloid pathology as well as in the inflammatory profile and reduced synaptic density, indicating that astrocytes mediate neuroprotective effects. The idea that interventions targeting astrocytes may have great potential for AD has therefore emerged, supported by a range of drugs and stem cell transplantation studies that have successfully shown a therapeutic effect in mouse models of AD. In this article, we review the latest reports on the role and profile of astrocytes in AD brains and how manipulation of astrocytes in animal mod- els has paved the way for the use of treatments enhancing astrocytic function as future therapeutic avenues for AD.

Clinical Characteristic in Primary Progressive Aphasia in Relation to Alzheimer’s Disease Biomarkers

2021 ◽  
pp. 1-13
Author(s):  
Sung Hoon Kang ◽  
Hanna Cho ◽  
Jiho Shin ◽  
Hang-Rai Kim ◽  
Young Noh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Language Impairment ◽  
Amyloid Β ◽  
Primary Progressive Aphasia ◽  
Cortical Atrophy ◽  
Clinical Feature ◽  
Progressive Aphasia ◽  
Disease Biomarkers ◽  
Primary Progressive

Background: Primary progressive aphasia (PPA) is associated with amyloid-β (Aβ) pathology. However, clinical feature of PPA based on Aβ positivity remains unclear. Objective: We aimed to assess the prevalence of Aβ positivity in patients with PPA and compare the clinical characteristics of patients with Aβ-positive (A+) and Aβ-negative (A–) PPA. Further, we applied Aβ and tau classification system (AT system) in patients with PPA for whom additional information of in vivo tau biomarker was available. Methods: We recruited 110 patients with PPA (41 semantic [svPPA], 27 non-fluent [nfvPPA], 32 logopenic [lvPPA], and 10 unclassified [ucPPA]) who underwent Aβ-PET imaging at multi centers. The extent of language impairment and cortical atrophy were compared between the A+ and A–PPA subgroups using general linear models. Results: The prevalence of Aβ positivity was highest in patients with lvPPA (81.3%), followed by ucPPA (60.0%), nfvPPA (18.5%), and svPPA (9.8%). The A+ PPA subgroup manifested cortical atrophy mainly in the left superior temporal/inferior parietal regions and had lower repetition scores compared to the A–PPA subgroup. Further, we observed that more than 90%(13/14) of the patients with A+ PPA had tau deposition. Conclusion: Our findings will help clinicians understand the patterns of language impairment and cortical atrophy in patients with PPA based on Aβ deposition. Considering that most of the A+ PPA patents are tau positive, understanding the influence of Alzheimer’s disease biomarkers on PPA might provide an opportunity for these patients to participate in clinical trials aimed for treating atypical Alzheimer’s disease.

scholarly journals Similar amyloid-β burden in posterior cortical atrophy and Alzheimer's disease

Brain ◽  
2011 ◽  
Vol 134 (7) ◽  
pp. 2036-2043 ◽  
Author(s):  
Leonardo Cruz de Souza ◽  
Fabian Corlier ◽  
Marie-Odile Habert ◽  
Olga Uspenskaya ◽  
Renaud Maroy ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Cortical Atrophy ◽  
Posterior Cortical Atrophy

scholarly journals Hyperactivity Induced by Soluble Amyloid-β Oligomers in the Early Stages of Alzheimer's Disease

2021 ◽  
Vol 13 ◽  
Author(s):  
Audrey Hector ◽  
Jonathan Brouillette
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Mechanisms ◽  
Clinical Symptoms ◽  
Epileptiform Activity ◽  
Amyloid Β ◽  
Gamma Oscillations ◽  
Synaptic Activity ◽  
Early Stages ◽  
The Impact

Soluble amyloid-beta oligomers (Aβo) start to accumulate in the human brain one to two decades before any clinical symptoms of Alzheimer's disease (AD) and are implicated in synapse loss, one of the best predictors of memory decline that characterize the illness. Cognitive impairment in AD was traditionally thought to result from a reduction in synaptic activity which ultimately induces neurodegeneration. More recent evidence indicates that in the early stages of AD synaptic failure is, at least partly, induced by neuronal hyperactivity rather than hypoactivity. Here, we review the growing body of evidence supporting the implication of soluble Aβo on the induction of neuronal hyperactivity in AD animal models, in vitro, and in humans. We then discuss the impact of Aβo-induced hyperactivity on memory performance, cell death, epileptiform activity, gamma oscillations, and slow wave activity. We provide an overview of the cellular and molecular mechanisms that are emerging to explain how Aβo induce neuronal hyperactivity. We conclude by providing an outlook on the impact of hyperactivity for the development of disease-modifying interventions at the onset of AD.

scholarly journals Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

2020 ◽  
Author(s):  
Michael J. Lucas ◽  
Henry S. Pan ◽  
Eric J. Verbeke ◽  
Lauren J. Webb ◽  
David W. Taylor ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
De Novo ◽  
Amyloid Β ◽  
Mesoporous Silicas ◽  
Aggregation Kinetics ◽  
Central Feature ◽  
Relative Population ◽  
Aβ Fibrils

AbstractThe aggregation of Amyloid-β (Aβ) is associated with the onset of Alzheimer’s Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of Aβ1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from Aβ1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Aβ1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of Aβ1-40 and other amyloidogenic proteins.Significance StatementA major challenge in understanding the progression of Alzheimer’s Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-β (Aβ). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that Aβ fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of Aβ1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of Aβ fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific Aβ polymorphs.

scholarly journals Relationship between cortical iron and tau aggregation in Alzheimer’s disease

Brain ◽  
2020 ◽  
Vol 143 (5) ◽  
pp. 1341-1349 ◽  
Author(s):  
Nicola Spotorno ◽  
Julio Acosta-Cabronero ◽  
Erik Stomrud ◽  
Björn Lampinen ◽  
Olof T Strandberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Critical Role ◽  
Disease Process ◽  
Amyloid Β ◽  
Cortical Atrophy ◽  
Tau Pet ◽  
Tau Aggregation ◽  
The Relationship

Abstract A growing body of evidence suggests that the dysregulation of neuronal iron may play a critical role in Alzheimer’s disease. Recent MRI studies have established a relationship between iron accumulation and amyloid-β aggregation. The present study provides further insight demonstrating a relationship between iron and tau accumulation using magnetic resonance-based quantitative susceptibility mapping and tau-PET in n = 236 subjects with amyloid-β pathology (from the Swedish BioFINDER-2 study). Both voxel-wise and regional analyses showed a consistent association between differences in bulk magnetic susceptibility, which can be primarily ascribed to an increase in iron content, and tau-PET signal in regions known to be affected in Alzheimer’s disease. Subsequent analyses revealed that quantitative susceptibility specifically mediates the relationship between tau-PET and cortical atrophy measures, thus suggesting a modulatory effect of iron burden on the disease process. We also found evidence suggesting the relationship between quantitative susceptibility and tau-PET is stronger in younger participants (age ≤ 65). Together, these results provide in vivo evidence of an association between iron deposition and both tau aggregation and neurodegeneration, which help advance our understanding of the role of iron dysregulation in the Alzheimer’s disease aetiology.

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 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 Comparative Analysis of Different Definitions of Amyloid-β Positivity to Detect Early Downstream Pathophysiological Alterations in Preclinical Alzheimer

2020 ◽  
pp. 1-10
Author(s):  
M. Milà-Alomà ◽  
G. Salvadó ◽  
M. Shekari ◽  
O. Grau-Rivera ◽  
A. Sala-Vila ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Comparative Analysis ◽  
Amyloid Β ◽  
Csf Biomarkers ◽  
Optimal Detection ◽  
Preclinical Stage ◽  
Positive Group ◽  
Early Stages ◽  
T Tau

Amyloid-β (Aβ) positivity is defined using different biomarkers and different criteria. Criteria used in symptomatic patients may conceal meaningful early Aβ pathology in preclinical Alzheimer. Therefore, the description of sensitive cutoffs to study the pathophysiological changes in early stages of the Alzheimer’s continuum is critical. Here, we compare different Aβ classification approaches and we show their performance in detecting pathophysiological changes downstream Aβ pathology. We studied 368 cognitively unimpaired individuals of the ALFA+ study, many of whom in the preclinical stage of the Alzheimer’s continuum. Participants underwent Aβ PET and CSF biomarkers assessment. We classified participants as Aβ -positive using five approaches: (1) CSF Aβ42 < 1098 pg/ml; (2) CSF Aβ42/40 < 0.071; (3) Aβ PET Centiloid > 12; (4) Aβ PET Centiloid > 30 or (5) Aβ PET Positive visual read. We assessed the correlations between Aβ biomarkers and compared the prevalence of Aβ positivity. We determined which approach significantly detected associations between Aβ pathology and tau/neurodegeneration CSF biomarkers. We found that CSF-based approaches result in a higher Aβ-positive prevalence than PET-based ones. There was a higher number of discordant participants classified as CSF Aβ-positive but PET Aβ-negative than CSF Aβ-negative but PET Aβ-positive. The CSF Aβ 42/40 approach allowed optimal detection of significant associations with CSF p-tau and t-tau in the Aβ-positive group. Altogether, we highlight the need for sensitive Aβ -classifications to study the preclinical Alzheimer’s continuum. Approaches that define Aβ positivity based on optimal discrimination of symptomatic Alzheimer’s disease patients may be suboptimal for the detection of early pathophysiological alterations in preclinical Alzheimer.

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