scholarly journals Coexisting order and disorder within a common 40-residue amyloid-β fibril structure in Alzheimer's disease brain tissue

2018 ◽  
Vol 54 (40) ◽  
pp. 5070-5073 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Amyloid Β ◽  
Order And Disorder ◽  
Fibril Structure

Only about half of the 40-residue amyloid-β sequence is structurally ordered in a common fibril structure from Alzheimer's disease brain.

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

2021 ◽  
Vol 118 (4) ◽  
pp. e2023089118 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Molecular Conformations ◽  
Layered Architecture ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils ◽  
Β Sheet

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Targeting the amyloid-β antibody in the brain tissue of a mouse model of Alzheimer's disease

2012 ◽  
Vol 159 (2) ◽  
pp. 302-308 ◽  
Author(s):  
Daniel McLean ◽  
Michael J. Cooke ◽  
Yuanfei Wang ◽  
Paul Fraser ◽  
Peter St George-Hyslop ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Brain Tissue ◽  
Amyloid Β ◽  
Model Of Alzheimer’S Disease ◽  
The Brain

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer’s disease brain tissue

2020 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Conformation ◽  
Amyloid Β ◽  
Cryo Electron Microscopy ◽  
Nmr Data ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils

AbstractAmyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may underlie variations in clinical and pathological characteristics of Alzheimer’s disease. We report the molecular structure of a specific brain-derived polymorph that has been identified as the most prevalent polymorph of 40-residue Aβ fibrils in cortical tissue of Alzheimer’s disease patients. This structure, developed from cryo-electron microscopy and supported by solid state NMR data, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformation and its organization of cross-β subunits. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

scholarly journals Clinical Approach of Low-Dose Whole-Brain Ionizing Radiation Treatment in Alzheimer’s Disease Dementia Patients

2021 ◽  
pp. 1-7
Author(s):  
Mijoo Chung ◽  
Weon Kuu Chung
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Tissue ◽  
Inflammatory Cytokine ◽  
Low Dose ◽  
Transforming Growth Factor ◽  
Amyloid Β ◽  
Clinical Results ◽  
Clinical Approach ◽  
Alzheimer’S Disease Dementia

Our research team recently published two relevant papers. In one study, we have seen the acute effect of low-dose ionizing irradiation (LDIR) did not reduce the amyloid-β (Aβ) protein concentration in brain tissue, yet significantly improved synaptic degeneration and neuronal loss in the hippocampus and cerebral cortex. Surprisingly, in another study, we could see late effect that the LDIR-treated mice showed significantly improved learning and memory skills compared with those in the sham group. In addition, Aβ concentrations were significantly decreased in brain tissue. Furthermore, the pro-inflammatory cytokine tumor necrosis factor-α was decreased and the anti-inflammatory cytokine transforming growth factor-β was increased in the brain tissue of 5xFAD mice treated with LDIR. Definitive clinical results for the safety and efficacy of LDIR have not yet been published and, despite the promising outcomes reported during preclinical studies, LDIR can only be applied to patients with Alzheimer’s disease dementia when clinical results are made available. In addition, in the case of LDIR, additional large-scale clinical studies are necessary to determine the severity of Alzheimer’s disease dementia, indications for LDIR, the total dose to be irradiated, fraction size, and intervals of LDIR treatment. The purpose of this review is to summarize the mechanism of LDIR based on existing preclinical results in a way that is useful for conducting subsequent clinical research.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

Neuroinflammation and Complexes of 17β -Hydroxysteroid Dehydrogenase type 10 - Amyloid β in Alzheimer's Disease

2013 ◽  
Vol 10 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Zdena Kristofikova ◽  
Daniela Ripova ◽  
Ales Bartos ◽  
Marketa Bockova ◽  
Katerina Hegnerova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Hydroxysteroid Dehydrogenase

Microglia in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 29-43 ◽  
Author(s):  
Patrick Süß ◽  
Johannes C.M. Schlachetzki
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Current Knowledge ◽  
Imaging Techniques ◽  
Amyloid Β ◽  
Disease Stage ◽  
Disease Modifying Therapy ◽  
Transcriptomic Signature

: Alzheimer’s Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. : In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models.

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