Fibrillization of 40-residue β-Amyloid Peptides in Membrane-Like Environments Leads to Different Fibril Structures and Reduced Molecular Polymorphisms

The molecular-level polymorphism in β-Amyloid (Aβ) fibrils have recently been considered as a pathologically relevant factor in Alzheimer’s disease (AD). Studies showed that the structural deviations in human-brain-seeded Aβ fibrils potentially correlated with the clinical histories of AD patients. For the 40-residue Aβ (Aβ40) fibrils derived from human brain tissues, a predominant molecular structure was proposed based on solid-state nuclear magnetic resonance (ssNMR) spectroscopy. However, previous studies have shown that the molecular structures of Aβ40 fibrils were sensitive to their growth conditions in aqueous environments. We show in this work that biological membranes and their phospholipid bilayer mimics serve as environmental factors to reduce the structural heterogeneity in Aβ40 fibrils. Fibrillization in the presence of membranes leads to fibril structures that are significantly different to the Aβ40 fibrils grown in aqueous solutions. Fibrils grown from multiple types of membranes, including the biological membranes extracted from the rats’ synaptosomes, shared similar ssNMR spectral features. Our studies emphasize the biological relevance of membranes in Aβ40 fibril structures and fibrillization processes.

Download Full-text

Amino- and carboxyl-terminal heterogeneity of β-amyloid peptides deposited in human brain

Neuroscience Letters ◽

10.1016/0304-3940(96)12970-0 ◽

1996 ◽

Vol 215 (3) ◽

pp. 173-176 ◽

Cited By ~ 178

Author(s):

Takaomi C. Saido ◽

Wakako Yamao-Harigaya ◽

Takeshi Iwatsubo ◽

Seiichi Kawashima

Keyword(s):

Human Brain ◽

Amyloid Peptides ◽

Β Amyloid ◽

Carboxyl Terminal

Download Full-text

Deleterious effects of combination of lead and β-amyloid peptides in inducing apoptosis and altering cell cycle in human neuroblastoma cells

Interdisciplinary Toxicology ◽

10.1515/intox-2017-0015 ◽

2017 ◽

Vol 10 (3) ◽

pp. 93-98 ◽

Cited By ~ 2

Author(s):

Ayyalasomayajula Neelima ◽

Ajumeera Rajanna ◽

Reddy G. Bhanuprakash ◽

C.S. Chetty ◽

Challa Suresh

Keyword(s):

Alzheimer’S Disease ◽

Cell Cycle ◽

Human Brain ◽

Neuroblastoma Cells ◽

Brain Cells ◽

Human Neuroblastoma Cells ◽

Human Neuroblastoma ◽

Amyloid Peptides ◽

Β Amyloid ◽

The Brain

AbstractLead (Pb) is a toxic pollutant known to cause several abnormalities related to the brain, including cognitive dysfunction, and it is ubiquitous in nature. β-amyloid peptides (AP) are crucially involved in Alzheimer’s disease (AD). It has been reported that there is a connection between lead and amyloid peptides in exerting similar kinds of altered functions in the brain and long-term exposure to lead leads ultimately to increased beta amyloid formation in the brain, lethal to human brain cells. There is still a lack of information on the mechanism by which Pb affects AP formation, exerting combined toxicity in AD patients. To fill the gap, we have systematically analyzed the toxicity individually and in combination of Pb and AP in human brain cells. We found that the combination of Pb and AP exerted a higher toxicity than individual exposures in human neuroblastoma cells. The lower inhibitory concentration values were determined by both time and concentration dependent manner on using MTT assay. The data resulted in the development of enhanced toxicity on exposure to Pb with both the combinations of AP(1-40) or (25-35) and with all combinations in human brain cells compared to individual exposures to Pb (1-40) or AP(25-35). The severe apoptotic effect and alteration in cell cycle by arresting at the S-phase evidenced the increased toxicity of combinational exposure to Pb and AP on human neuroblastoma cells. Furthermore, the quantitative determination of LDH and caspase-3 activity indicated the induction of severe toxicity. We conclude that both are synergistically associated with effects such as arresting the cell cycle and triggering apoptosis during the progression of Alzheimer’s disease.

Download Full-text

Membrane-disordering effects of β-amyloid peptides

Biochemical Society Transactions ◽

10.1042/bst0290617 ◽

2001 ◽

Vol 29 (4) ◽

pp. 617-623 ◽

Cited By ~ 49

Author(s):

W. E. Müller ◽

C. Kirsch ◽

G. P. Eckert

Keyword(s):

Cell Membranes ◽

Biological Effects ◽

Senile Plaques ◽

Initial Step ◽

Phospholipid Bilayer ◽

Membrane Properties ◽

Major Constituent ◽

Amyloid Peptides ◽

Low Concentrations ◽

Β Amyloid

β-Amyloid (Aβ) protein is the major constituent of senile plaques and cerebrovascular deposits characteristic of Alzheimer's disease (AD). The causal relationship between Aβ and AD-specific lesions like neurodegeneration and atrophy is still not known. The present article summarizes our studies indicating that rather low concentrations of Aβ significantly alter the fluidity of cell membranes and subcellular fractions from different tissues and different species including humans, as a possible initial step of its biological effects. Using different fluorescent probes our data show clearly that Aβ peptides specifically disturb the acylchain layer of cell membranes in a very distinct fashion. By contrast, membrane properties at the level of the polar heads of the phospholipid bilayer at the interface with membrane proteins are much less affected.

Download Full-text

Effects of β-amyloid peptides on the fluidity of membranes from frontal and parietal lobes of human brain. High potencies of Aβ1-42 and Aβ1-43

Amyloid ◽

10.3109/13506129809007284 ◽

1998 ◽

Vol 5 (1) ◽

pp. 10-15 ◽

Cited By ~ 35

Author(s):

W. E. Muller ◽

G. P. Eckert ◽

K. Scheuer ◽

N. J. Cairns ◽

A. Maras ◽

...

Keyword(s):

Human Brain ◽

Amyloid Peptides ◽

Parietal Lobes ◽

Β Amyloid ◽

Fluidity Of Membranes

Download Full-text

Tau-dependent microtubule disassembly initiated by prefibrillar β-amyloid

The Journal of Cell Biology ◽

10.1083/jcb.200605187 ◽

2006 ◽

Vol 175 (4) ◽

pp. 541-546 ◽

Cited By ~ 142

Author(s):

Michelle E. King ◽

Ho-Man Kan ◽

Peter W. Baas ◽

Alev Erisir ◽

Charles G. Glabe ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Active Region ◽

Transgenic Mice ◽

Cultured Cells ◽

Cultured Neurons ◽

Terminal Domain ◽

Biological Event ◽

Amyloid Aβ ◽

Β Amyloid ◽

Aβ Fibrils

Alzheimer's Disease (AD) is defined histopathologically by extracellular β-amyloid (Aβ) fibrils plus intraneuronal tau filaments. Studies of transgenic mice and cultured cells indicate that AD is caused by a pathological cascade in which Aβ lies upstream of tau, but the steps that connect Aβ to tau have remained undefined. We demonstrate that tau confers acute hypersensitivity of microtubules to prefibrillar, extracellular Aβ in nonneuronal cells that express transfected tau and in cultured neurons that express endogenous tau. Prefibrillar Aβ42 was active at submicromolar concentrations, several-fold below those required for equivalent effects of prefibrillar Aβ40, and microtubules were insensitive to fibrillar Aβ. The active region of tau was localized to an N-terminal domain that does not bind microtubules and is not part of the region of tau that assembles into filaments. These results suggest that a seminal cell biological event in AD pathogenesis is acute, tau-dependent loss of microtubule integrity caused by exposure of neurons to readily diffusible Aβ.

Download Full-text

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

10.26434/chemrxiv.12445505 ◽

2020 ◽

Author(s):

Liang Sun ◽

Anuj K. Sharma ◽

Byung-Hee Han ◽

Liviu M. Mirica

Keyword(s):

Reactive Oxygen Species ◽

Metal Ions ◽

Antioxidant Properties ◽

Reactive Oxygen ◽

Amyloid Plaques ◽

Transition Metal Ions ◽

Oxygen Species ◽

High Affinity ◽

Amyloid Aβ ◽

Β Amyloid

Alzheimer's disease (AD) is the most common neurodegenerative disorder, yet the cause and progression of this disorder are not completely understood. While the main hallmark of AD is the deposition of amyloid plaques consisting of the β-amyloid (Aβ) peptide, transition metal ions are also known to play a significant role in disease pathology by expediting the formation of neurotoxic soluble β-amyloid (Aβ) oligomers, reactive oxygen species (ROS), and oxidative stress. Thus, bifunctional metal chelators that can control these deleterious properties are highly desirable. Herein, we show that amentoflavone (AMF) – a natural biflavonoid compound, exhibits good metal-chelating properties, especially for chelating Cu2+ with very high affinity (pCu7.4 = 10.44). In addition, AMF binds to Aβ fibrils with a high affinity (Ki = 287 ± 20 nM) – as revealed by a competition thioflavin T (ThT) assay, and specifically labels the amyloid plaques ex vivo in the brain sections of transgenic AD mice – as confirmed via immunostaining with an Ab antibody. The effect of AMF on Aβ42 aggregation and disaggregation of Aβ42 fibrils was also investigated, to reveal that AMF can control the formation of neurotoxic soluble Aβ42 oligomers, both in absence and presence of metal ions, and as confirmed via cell toxicity studies. Furthermore, an ascorbate consumption assay shows that AMF exhibits potent antioxidant properties and can chelate Cu2+ and significantly diminish the Cu2+-ascorbate redox cycling and reactive oxygen species (ROS) formation. Overall, these studies strongly suggest that AMF acts as a bifunctional chelator that can interact with various Aβ aggregates and reduce their neurotoxicity, can also bind Cu2+ and mediate its deleterious redox properties, and thus AMF has the potential to be a lead compound for further therapeutic agent development for AD.

Download Full-text

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

Current Neurovascular Research ◽

10.2174/1567202617666200128141938 ◽

2020 ◽

Vol 17 (1) ◽

pp. 93-101 ◽

Cited By ~ 3

Author(s):

Dan Wang ◽

Zhifu Fei ◽

Song Luo ◽

Hai Wang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transgenic Mice ◽

Western Blot ◽

Mrna Expression ◽

Cognitive Deficits ◽

Protein Levels ◽

Amyloid Aβ ◽

Β Amyloid ◽

The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

Download Full-text

Long-Term Caloric Restriction Attenuates β-Amyloid Neuropathology and Is Accompanied by Autophagy in APPswe/PS1delta9 Mice

Nutrients ◽

10.3390/nu13030985 ◽

2021 ◽

Vol 13 (3) ◽

pp. 985

Author(s):

Luisa Müller ◽

Nicole Power Guerra ◽

Jan Stenzel ◽

Claire Rühlmann ◽

Tobias Lindner ◽

...

Keyword(s):

Caloric Restriction ◽

Neuroprotective Effect ◽

Resonance Spectroscopy ◽

Neuroprotective Effects ◽

Beneficial Effects ◽

Positron Emission ◽

Pet Ct ◽

Amyloid Aβ ◽

Β Amyloid

Caloric restriction (CR) slows the aging process, extends lifespan, and exerts neuroprotective effects. It is widely accepted that CR attenuates β-amyloid (Aβ) neuropathology in models of Alzheimer’s disease (AD) by so-far unknown mechanisms. One promising process induced by CR is autophagy, which is known to degrade aggregated proteins such as amyloids. In addition, autophagy positively regulates glucose uptake and may improve cerebral hypometabolism—a hallmark of AD—and, consequently, neural activity. To evaluate this hypothesis, APPswe/PS1delta9 (tg) mice and their littermates (wild-type, wt) underwent CR for either 16 or 68 weeks. Whereas short-term CR for 16 weeks revealed no noteworthy changes of AD phenotype in tg mice, long-term CR for 68 weeks showed beneficial effects. Thus, cerebral glucose metabolism and neuronal integrity were markedly increased upon 68 weeks CR in tg mice, indicated by an elevated hippocampal fluorodeoxyglucose [18F] ([18F]FDG) uptake and increased N-acetylaspartate-to-creatine ratio using positron emission tomography/computer tomography (PET/CT) imaging and magnet resonance spectroscopy (MRS). Improved neuronal activity and integrity resulted in a better cognitive performance within the Morris Water Maze. Moreover, CR for 68 weeks caused a significant increase of LC3BII and p62 protein expression, showing enhanced autophagy. Additionally, a significant decrease of Aβ plaques in tg mice in the hippocampus was observed, accompanied by reduced microgliosis as indicated by significantly decreased numbers of iba1-positive cells. In summary, long-term CR revealed an overall neuroprotective effect in tg mice. Further, this study shows, for the first time, that CR-induced autophagy in tg mice accompanies the observed attenuation of Aβ pathology.

Download Full-text

β-Amyloid Peptides Manipulate Switching Behaviors of Donor–Acceptor Stenhouse Adducts

Analytical Chemistry ◽

10.1021/acs.analchem.1c01957 ◽

2021 ◽

Author(s):

Chao Zheng ◽

Yue Yu ◽

Shi Kuang ◽

Biyue Zhu ◽

Heng Zhou ◽

...

Keyword(s):

Amyloid Peptides ◽

Donor Acceptor ◽

Β Amyloid

Download Full-text

Aging-associated deficit in CCR7 is linked to worsened glymphatic function, cognition, neuroinflammation, and β-amyloid pathology

Science Advances ◽

10.1126/sciadv.abe4601 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabe4601

Author(s):

Sandro Da Mesquita ◽

Jasmin Herz ◽

Morgan Wall ◽

Taitea Dykstra ◽

Kalil Alves de Lima ◽

...

Keyword(s):

T Cells ◽

Cognitive Decline ◽

Brain Aging ◽

Therapeutic Potential ◽

T Cell Response ◽

Age Related ◽

Lymphatic Vasculature ◽

Amyloid Aβ ◽

Β Amyloid ◽

Old Mice

Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)–dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer’s disease–like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.

Download Full-text