scholarly journals Structural biology of Alzheimer's disease

2014 ◽  
Vol 70 (a1) ◽  
pp. C698-C698
Author(s):  
Luke Miles ◽  
Gabriela Crespi ◽  
Tracy Nero ◽  
Michael Parker
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cross Reactivity ◽  
Soluble Form ◽  
Plaque Burden ◽  
Breakdown Product ◽  
Pathological Feature ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
N Terminus

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in humans with age being the biggest risk factor. The mechanisms by which the disease progresses to cognitive decline in the sufferer are complex and not fully elucidated. A defining pathological feature is the deposition of extracellular plaques composed primarily of misfolded amyloid beta (Aβ) peptide: a proteolytic breakdown product of the much larger Amyloid Precursor Protein. While Aβ peptides are the main constituents of amyloid plaques that burden the diseased brain, plaque burden correlates poorly with the severity of the disease. There is accumulating evidence that a prefibrillar or protofibrillar soluble form of Aβ can compromise neuronal functions and trigger cell death. Immunotherapy targeting Abeta is a promising direction in AD research with active and passive immunotherapies shown to lower cerebral Aβ levels and rescue cognitive function in animal models. Anti-Aβ immunotherapies are a significant class of AD therapeutics currently in human clinical trials. We have been examining the molecular basis of antibody engagement of Aβ epitopes to inform the analysis of clinical trial data and to guide the engineering of anti-Aβ antibodies with optimised specificity and affinity. We have determined the structures of three different AD antibodies in complex with Ab peptides: (1) WO2, which recognises the N-terminus of Aβ, (2) Mab 2286, which like the AD immunotherapeutic Ponezumab (Pfizer), shows specificity for the C-terminus of Aβ40 but has no significant cross-reactivity with Aβ42/43, and (3) Bapineuzumab, a humanized antibody developed by Pfizer and Johnson & Johnson which recognises the N-terminus of Aβ but cannot recognize N-terminally modified or truncated Aβ peptides (1). All these studies reveal surprising aspects of Aβ peptide recognition by the antibodies and suggest new avenues for AD antibody development.

scholarly journals The Function of Transthyretin Complexes with Metallothionein in Alzheimer’s Disease

2020 ◽  
Vol 21 (23) ◽  
pp. 9003
Author(s):  
Natalia Zaręba ◽  
Marta Kepinska
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cortical Neurons ◽  
The Elderly ◽  
Pathological Feature ◽  
Aβ Peptides ◽  
Treatment And Prevention ◽  
Aβ Aggregation ◽  
Cultured Cortical Neurons ◽  
Amyloid Aβ

Alzheimer’s disease (AD) is one of the most frequently diagnosed types of dementia in the elderly. An important pathological feature in AD is the aggregation and deposition of the β-amyloid (Aβ) in extracellular plaques. Transthyretin (TTR) can cleave Aβ, resulting in the formation of short peptides with less activity of amyloid plaques formation, as well as being able to degrade Aβ peptides that have already been aggregated. In the presence of TTR, Aβ aggregation decreases and toxicity of Aβ is abolished. This may prevent amyloidosis but the malfunction of this process leads to the development of AD. In the context of Aβplaque formation in AD, we discuss metallothionein (MT) interaction with TTR, the effects of which depend on the type of MT isoform. In the brains of patients with AD, the loss of MT-3 occurs. On the contrary, MT-1/2 level has been consistently reported to be increased. Through interaction with TTR, MT-2 reduces the ability of TTR to bind to Aβ, while MT-3 causes the opposite effect. It increases TTR-Aβ binding, providing inhibition of Aβ aggregation. The protective effect, assigned to MT-3 against the deposition of Aβ, relies also on this mechanism. Additionally, both Zn7MT-2 and Zn7MT-3, decrease Aβ neurotoxicity in cultured cortical neurons probably because of a metal swap between Zn7MT and Cu(II)Aβ. Understanding the molecular mechanism of metals transfer between MT and other proteins as well as cognition of the significance of TTR interaction with different MT isoforms can help in AD treatment and prevention.

Evaluation of a Possible Role of Stigmatella aurantiaca ACE in Aβ Peptide Degradation: A Molecular Modeling Approach

2015 ◽  
Vol 25 (1) ◽  
pp. 26-36 ◽  
Author(s):  
Chidambar B. Jalkute ◽  
Kailas D. Sonawane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Three Dimensional ◽  
Amyloid Β ◽  
Dynamics Simulation ◽  
Aβ Peptide ◽  
Three Dimensional Model ◽  
Aβ Peptides ◽  
Simulation Techniques ◽  
Stigmatella Aurantiaca

Amyloid-β (Aβ)-degrading enzymes are known to degrade Aβ peptides, a causative agent of Alzheimer's disease. These enzymes are responsible for maintaining Aβ concentration. However, loss of such enzymes or their Aβ-degrading activity because of certain genetic as well as nongenetic reasons initiates the accumulation of Aβ peptides in the human brain. Considering the limitations of the human enzymes in clearing Aβ peptide, the search for microbial enzymes that could cleave Aβ is necessary. Hence, we built a three-dimensional model of angiotensin-converting enzyme (ACE) from <i>Stigmatella aurantiaca</i> using homology modeling technique. Molecular docking and molecular dynamics simulation techniques were used to outline the possible cleavage mechanism of Aβ peptide. These findings suggest that catalytic residue Glu 434 of the model could play a crucial role to degrade Aβ peptide between Asp 7 and Ser 8. Thus, ACE from <i>S. aurantiaca</i> might cleave Aβ peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.

scholarly journals Down-regulation of cyclin D2 in amyloid β toxicity, inflammation, and Alzheimer’s disease

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259740
Author(s):  
Grzegorz A. Czapski ◽  
Magdalena Cieślik ◽  
Emilia Białopiotrowicz ◽  
Walter J. Lukiw ◽  
Joanna B. Strosznajder
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Aβ Peptide ◽  
Cyclin Dependent Kinase ◽  
Wild Type ◽  
Cyclin D2 ◽  
Aβ Peptides ◽  
Expression Of Genes ◽  
Genes Encoding

In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer’s disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated. Cyclin cD2 was also found to be down-regulated in AD neocortex and hippocampus. Our novel data indicate that Aβ peptide and inflammation both significantly decreased the expression of cD2, suggesting that Aβ peptides may also contribute to downregulation of cD2 in AD brain.

Insight into molecular interactions of Aβ peptide and gelatinase from Enterococcus faecalis: a molecular modeling approach

RSC Advances ◽  
2015 ◽  
Vol 5 (14) ◽  
pp. 10488-10496 ◽  
Author(s):  
Chidambar B. Jalkute ◽  
Sagar H. Barage ◽  
Kailas D. Sonawane
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Modeling ◽  
Enterococcus Faecalis ◽  
Amyloid Beta ◽  
Molecular Interactions ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Modeling Approach ◽  
Insight Into

Alzheimer's disease is characterized by the presence of extracellular deposition of amyloid beta (Aβ) peptides.

scholarly journals Natural Products Targeting Amyloid Beta in Alzheimer’s Disease

2021 ◽  
Vol 22 (5) ◽  
pp. 2341
Author(s):  
Joo-Hee Lee ◽  
Na-Hyun Ahn ◽  
Su-Bin Choi ◽  
Youngeun Kwon ◽  
Seung-Hoon Yang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Natural Products ◽  
Amyloid Beta ◽  
Conformational Changes ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Peptide Formation ◽  
Current Clinical Trial

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by severe brain damage and dementia. There are currently few therapeutics to treat this disease, and they can only temporarily alleviate some of the symptoms. The pathogenesis of AD is mainly preceded by accumulation of abnormal amyloid beta (Aβ) aggregates, which are toxic to neurons. Therefore, modulation of the formation of these abnormal aggregates is strongly suggested as the most effective approach to treat AD. In particular, numerous studies on natural products associated with AD, aiming to downregulate Aβ peptides and suppress the formation of abnormal Aβ aggregates, thus reducing neural cell death, are being conducted. Generation of Aβ peptides can be prevented by targeting the secretases involved in Aβ-peptide formation (secretase-dependent). Additionally, blocking the intra- and intermolecular interactions of Aβ peptides can induce conformational changes in abnormal Aβ aggregates, whereby the toxicity can be ameliorated (structure-dependent). In this review, AD-associated natural products which can reduce the accumulation of Aβ peptides via secretase- or structure-dependent pathways, and the current clinical trial states of these products are discussed.

scholarly journals The protective mutation A673T in amyloid precursor protein gene decreases Aβ peptides production for 14 forms of Familial Alzheimer’s Disease in SH-SY5Y cells

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0237122
Author(s):  
Antoine Guyon ◽  
Joël Rousseau ◽  
Gabriel Lamothe ◽  
Jacques P. Tremblay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Gene ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Amyloidogenic Processing ◽  
Icelandic Population ◽  
App Gene

The deposition of Aβ plaques in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is cleaved by α-secretase (non-amyloidogenic processing of APP), however increased cleavage by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms plaques. APP mutations mapping to exons 16 and 17 favor plaque accumulation and cause Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) originally found in an Icelandic population reduces BACE1 cleavage by 40%. A series of plasmids containing the APP gene, each with one of 29 different FAD mutations mapping to exon 16 and exon 17 was created. These plasmids were then replicated with the addition of the A673T mutation. Combined these formed the library of plasmids that was used in this study. The plasmids were transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. The production of Aβ peptides was decreased for some FAD mutations due to the presence of the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as for A673T control in SH-SY5Y cells. These preliminary results suggest that the insertion of A673T in APP genes containing FAD mutations might confer a clinical benefit in preventing or delaying the onset of some FADs.

scholarly journals Modelling the efficacy of Neprilysin from various species in degrading different Amyloid-β peptides: Potential application in therapeutics of Alzheimer’s disease

2021 ◽  
Author(s):  
Arun HS Kumar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Enzyme Kinetics ◽  
Molecular Interaction ◽  
Interaction Analysis ◽  
Amyloid Β ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Enzyme Substrate ◽  
Substrate Kinetics

AbstractRecombinant neprilysin due to its degradation potential against Amyloid-β (Aβ) peptides has been looked at as a potential therapeutic candidate for treating Alzheimer’s disease (AD). However the enzymatic activity of neprilysin against different Aβ peptides can variable which significantly limits the therapeutic optimization. Using the molecular interaction analysis and modelling it against the known enzyme-substrate kinetics, this study developed a novel approach to predicting biosimilar enzyme-substrate kinetics. The known enzyme-substrate kinetics of human recombinant neprilysin with Aβ1-40 peptide was used as the prototype to assess the affinity and efficacy of various inter and intra-species neprilysin- Aβ peptide enzyme kinetics based on the relative molecular interaction analysis. Significant inter and intra-species variations in neprilysin- Aβ peptide enzyme kinetics was observed which further validated the need for optimizing enzyme kinetics tailored to specific substrate degradation. The novel enzyme kinetics modelling approach described in this study can be helpful in the developing of recombinant enzymes/peptides for personalised therapeutic applications.

scholarly journals Protective mutation A673T as a potential gene therapy for most forms of APP Familial Alzheimer’s Disease

2020 ◽  
Author(s):  
Antoine Guyon ◽  
Joël Rousseau ◽  
Gabriel Lamothe ◽  
Jacques P. Tremblay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Gene Therapy ◽  
Alzheimer Disease ◽  
Gene Mutations ◽  
Aβ Peptide ◽  
Aβ Peptides ◽  
Familial Alzheimer Disease ◽  
App Gene ◽  
The Brain

AbstractThe accumulation of plaque in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is usually cut by α-secretase, however an abnormal cleavage profile by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms these plaques. Numerous APP gene mutations favor plaque accumulation, causing Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) in Icelanders reduces BACE1 cleavage by 40 %. A library of plasmids containing APP genes with 29 FAD mutations with or without the additional A673T mutation was generated and transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. In most cases the production of Aβ peptides was decreased by the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as A673T carriers. These results suggest that the insertion of A673T in the APP gene of genetically susceptible FAD patients may prevent the onset of, slow down, or stop the progression of the disease.

Ruthenium(II)–arene complexes with chelating quinoline ligands as anti-amyloid agents

2021 ◽  
pp. 1-7
Author(s):  
Cade J. Meiss ◽  
Paige J. Bothwell ◽  
Michael I. Webb
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metal Ions ◽  
Amyloid Beta ◽  
The Other ◽  
Soluble Form ◽  
Aβ Peptide ◽  
Arene Complexes ◽  
Therapeutic Development ◽  
Neurotoxic Agent

Recent recognition of the soluble form of the amyloid-beta (Aβ) peptide as a neurotoxic agent in Alzheimer’s disease (AD) has spurred the development of agents to target this species. Because Aβ is known to chelate metal ions in solution, metal-based therapeutics are uniquely suited to exploit this affinity, where coordination to Aβ has been shown to impact the neurotoxicity of the peptide. Ruthenium(II)–arene complexes are unique candidates for evaluation, as one face of the molecule is blocked by the hydrophobic arene ring, while coordination to the Aβ peptide can occur on the other side of the molecule. We have prepared and evaluated two Ru(II)–arene complexes with chelating quinoline-based ligands, Ru1 and Ru2, for their respective anti-amyloid abilities. Although both complexes decreased the aggregation of soluble Aβ, Ru1 displayed promise in disrupting formed aggregates of the peptide. These findings represent an exciting new avenue for therapeutic development in AD, where both sides of the aggregation equilibrium are affected.

The Role of Lipids and Membranes in the Pathogenesis of Alzheimer's Disease: A Comprehensive View

2018 ◽  
Vol 15 (13) ◽  
pp. 1191-1212 ◽  
Author(s):  
Botond Penke ◽  
Gábor Paragi ◽  
János Gera ◽  
Róbert Berkecz ◽  
Zsolt Kovács ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathways ◽  
Membrane Lipids ◽  
Specific Protein ◽  
Dietary Factors ◽  
Lipid Signaling ◽  
Special Role ◽  
Aβ Peptides

Lipids participate in Amyloid Precursor Protein (APP) trafficking and processing - important factors in the initiation of Alzheimer’s disease (AD) pathogenesis and influence the formation of neurotoxic β-amyloid (Aβ) peptides. An important risk factor, the presence of ApoE4 protein in AD brain cells binds the lipids to AD. In addition, lipid signaling pathways have a crucial role in the cellular homeostasis and depend on specific protein-lipid interactions. The current review focuses on pathological alterations of membrane lipids (cholesterol, glycerophospholipids, sphingolipids) and lipid metabolism in AD and provides insight in the current understanding of biological membranes, their lipid structures and functions, as well as their role as potential therapeutic targets. Novel methods for studying the membrane structure and lipid composition will be reviewed in a broad sense whereas the use of lipid biomarkers for early diagnosis of AD will be shortly summarized. Interactions of Aβ peptides with the cell membrane and different subcellular organelles are reviewed. Next, the details of the most important lipid signaling pathways, including the role of the plasma membrane as stress sensor and its therapeutic applications are given. 4-hydroxy-2-nonenal may play a special role in the initiation of the pathogenesis of AD and thus the “calpain-cathepsin hypothesis” of AD is highlighted. Finally, the most important lipid dietary factors and their possible use and efficacy in the prevention of AD are discussed.

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