scholarly journals Augmentation of Bri2 molecular chaperone activity against amyloid-β reduces neurotoxicity in mouse hippocampus in vitro

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Gefei Chen ◽  
Yuniesky Andrade-Talavera ◽  
Simone Tambaro ◽  
Axel Leppert ◽  
Harriet E. Nilsson ◽  
...  
Keyword(s):  
Molecular Chaperone ◽  
Molecular Chaperones ◽  
Quaternary Structure ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Network Activity ◽  
Amyloid Β Peptide ◽  
Neuronal Network Activity ◽  
Age Related

AbstractMolecular chaperones play important roles in preventing protein misfolding and its potentially harmful consequences. Deterioration of molecular chaperone systems upon ageing are thought to underlie age-related neurodegenerative diseases, and augmenting their activities could have therapeutic potential. The dementia relevant domain BRICHOS from the Bri2 protein shows qualitatively different chaperone activities depending on quaternary structure, and assembly of monomers into high-molecular weight oligomers reduces the ability to prevent neurotoxicity induced by the Alzheimer-associated amyloid-β peptide 1-42 (Aβ42). Here we design a Bri2 BRICHOS mutant (R221E) that forms stable monomers and selectively blocks a main source of toxic species during Aβ42 aggregation. Wild type Bri2 BRICHOS oligomers are partly disassembled into monomers in the presence of the R221E mutant, which leads to potentiated ability to prevent Aβ42 toxicity to neuronal network activity. These results suggest that the activity of endogenous molecular chaperones may be modulated to enhance anti-Aβ42 neurotoxic effects.

scholarly journals Amyloid β Peptide-Induced Changes in Prefrontal Cortex Activity and Its Response to Hippocampal Input

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Ernesto Flores-Martínez ◽  
Fernando Peña-Ortega
Keyword(s):  
Prefrontal Cortex ◽  
Brain Slices ◽  
Amyloid Β ◽  
Network Activity ◽  
Amyloid Β Peptide ◽  
Cell Level ◽  
Long Range Interactions ◽  
Induced Changes ◽  
The Brain

Alterations in prefrontal cortex (PFC) function and abnormalities in its interactions with other brain areas (i.e., the hippocampus) have been related to Alzheimer Disease (AD). Considering that these malfunctions correlate with the increase in the brain’s amyloid beta (Aβ) peptide production, here we looked for a causal relationship between these pathognomonic signs of AD. Thus, we tested whether or not Aβ affects the activity of the PFC network and the activation of this cortex by hippocampal input stimulation in vitro. We found that Aβ application to brain slices inhibits PFC spontaneous network activity as well as PFC activation, both at the population and at the single-cell level, when the hippocampal input is stimulated. Our data suggest that Aβ can contribute to AD by disrupting PFC activity and its long-range interactions throughout the brain.

scholarly journals A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tatsuya Ikenoue ◽  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Francesco S. Ruggeri ◽  
Michele Perni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Worm Model

Abstract Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

scholarly journals Neuroinflammatory changes increase the impact of stressors on neuronal function

2009 ◽  
Vol 37 (1) ◽  
pp. 303-307 ◽  
Author(s):  
Alessia Piazza ◽  
Marina A. Lynch
Keyword(s):  
Neurodegenerative Diseases ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Experimental Conditions ◽  
Age Related ◽  
Increased Risk ◽  
Aβ Amyloid ◽  
The Impact

In the last few years, several research groups have reported that neuroinflammation is one feature common to several neurodegenerative diseases and that similar, although perhaps less profound, neuroinflammatory changes also occur with age. Age is the greatest risk factor in many neurodegenerative diseases, and the possibility exists that the underlying age-related neuroinflammation may contribute to this increased risk. Several animal models have been used to examine this possibility, and it is now accepted that, under experimental conditions in which microglial activation is up-regulated, responses to stressors are exacerbated. In the present article, these findings are discussed and data are presented from in vitro and in vivo experiments which reveal that responses to Aβ (amyloid β-peptide) are markedly up-regulated in the presence of LPS (lipopolysaccharide). These, and previous findings, point to a vulnerability associated with inflammation and suggest that, even though inflammation may not be the primary cause of neurodegenerative disease, its treatment may decelerate disease progression.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

scholarly journals Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Felipe P. Perez ◽  
Bryan Maloney ◽  
Nipun Chopra ◽  
Jorge J. Morisaki ◽  
Debomoy K. Lahiri
Keyword(s):  
Electromagnetic Field ◽  
Late Onset ◽  
Amyloid Β ◽  
Clinical Settings ◽  
Amyloid Β Peptide ◽  
Field Stimulation ◽  
Amino Acid Residues ◽  
Hyperphosphorylated Tau Protein ◽  
Magnetic Resonance Imaging Mri

AbstractLate Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

Dementia with Lewy bodies—associated ß-synuclein mutations V70M and P123H cause mutation-specific neuropathological lesions

2021 ◽  
Author(s):  
Maryna Psol ◽  
Sofia Guerin Darvas ◽  
Kristian Leite ◽  
Sameehan U Mahajani ◽  
Mathias Bähr ◽  
...  
Keyword(s):  
Neuronal Network ◽  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Sporadic Case ◽  
Network Activity ◽  
Proteinase K ◽  
Neuronal Network Activity ◽  
Distinct Disease

Abstract ß-Synuclein (ß-Syn) has long been considered to be an attenuator for the neuropathological effects caused by the Parkinson’s disease-related α-Synuclein (α-Syn) protein. However, recent studies demonstrated that overabundant ß-Syn can form aggregates and induce neurodegeneration in CNS neurons in vitro and in vivo, albeit at a slower pace as compared to α-Syn. Here we demonstrate that ß-Syn mutants V70M, detected in a sporadic case of Dementia with Lewy Bodies (DLB), and P123H, detected in a familial case of DLB, robustly aggravate the neurotoxic potential of ß-Syn. Intriguingly, the two mutations trigger mutually exclusive pathways. ß-Syn V70M enhances morphological mitochondrial deterioration and degeneration of dopaminergic and non-dopaminergic neurons, but has no influence on neuronal network activity. Conversely, ß-Syn P123H silences neuronal network activity, but does not aggravate neurodegeneration. ß-Syn WT, V70M and P123H formed proteinase K (PK) resistant intracellular fibrils within neurons, albeit with less stable C-termini as compared to α-Syn. Under cell free conditions, ß-Syn V70M demonstrated a much slower pace of fibril formation as compared to WT ß-Syn, and P123H fibrils present with a unique phenotype characterized by large numbers of short, truncated fibrils. Thus, it is possible that V70M and P123H cause structural alterations in ß-Syn, that are linked to their distinct neuropathological profiles. The extent of the lesions caused by these neuropathological profiles is almost identical to that of overabundant α-Syn, and thus likely to be directly involved into etiology of DLB. Over all, this study provides insights into distinct disease mechanisms caused by mutations of ß-Syn.

scholarly journals Garlic Extract: Inhibition of Biochemical and Biophysical Changes in Glycated HSA

2021 ◽  
Vol 11 (22) ◽  
pp. 11028
Author(s):  
Mohd W. A. Khan ◽  
Ahmed A. Otaibi ◽  
Arwa F. M. Alhumaid ◽  
Abdulmohsen K. D. Alsukaibi ◽  
Asma K. Alshamari ◽  
...  
Keyword(s):  
Structural Changes ◽  
Therapeutic Potential ◽  
Inhibitory Effect ◽  
Significant Inhibition ◽  
Garlic Extract ◽  
Diabetic Patients ◽  
Age Related ◽  
Health Complications ◽  
Biophysical Changes

Glycation of various biomolecules contributes to structural changes and formation of several high molecular weight fluorescent and non-fluorescent, advanced glycation end products (AGEs). AGEs and glycation are involved in various health complications. Synthetic medicines, including metformin, have several adverse effects. Natural products and their derivatives are used in the treatment of various diseases due to their significant therapeutic qualities. Allium sativum (garlic) is used in traditional medicines because of its antioxidant, anti-inflammatory, and anti-diabetic properties. This study aimed to determine the anti-glycating and AGEs inhibitory activities of garlic. Biochemical and biophysical analyses were performed for in vitro incubated human serum albumin (HSA) with 0.05 M of glucose for 1, 5, and 10 weeks. Anti-glycating and AGEs inhibitory effect of garlic was investigated in glycated samples. Increased biochemical and biophysical changes were observed in glycated HSA incubated for 10 weeks (G-HSA-10W) as compared to native HSA (N-HSA) as well as glycated HSA incubated for 1 (G-HSA-1W) and 5 weeks (G-HSA-5W). Garlic extract with a concentration of ≥6.25 µg/mL exhibited significant inhibition in biophysical and biochemical changes of G-HSA-10W. Our findings demonstrated that garlic extract has the ability to inhibit biochemical and biophysical changes in HSA that occurred due to glycation. Thus, garlic extract can be used against glycation and AGE-related health complications linked with chronic diseases in diabetic patients due to its broad therapeutic potential.

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