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

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 Stigmatella aurantiaca 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 S. aurantiaca might cleave Aβ peptides similar to human ACE and could be used to design new therapeutic strategies against Alzheimer's disease.

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

PLoS ONE ◽

10.1371/journal.pone.0259740 ◽

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.

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

10.1101/2021.03.25.436981 ◽

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.

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A Super-Resolved View of the Alzheimer’s Disease-Related Amyloidogenic Pathway in Hippocampal Neurons

Journal of Alzheimer s Disease ◽

10.3233/jad-215008 ◽

2021 ◽

pp. 1-20

Author(s):

Yang Yu ◽

Yang Gao ◽

Bengt Winblad ◽

Lars Tjernberg ◽

Sophia Schedin Weiss

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Hippocampal Neurons ◽

Three Dimensional ◽

Amyloid Β ◽

Stimulated Emission ◽

Amyloid Β Peptide ◽

Primary Neurons ◽

Amyloid Β Protein ◽

Early Endosomes

Background: Processing of the amyloid-β protein precursor (AβPP) is neurophysiologically important due to the resulting fragments that regulate synapse biology, as well as potentially harmful due to generation of the 42 amino acid long amyloid β-peptide (Aβ 42), which is a key player in Alzheimer’s disease. Objective: Our aim was to clarify the subcellular locations of the amyloidogenic AβPP processing in primary neurons, including the intracellular pools of the immediate substrate, AβPP C-terminal fragment (APP-CTF) and the product (Aβ 42). To overcome the difficulties of resolving these compartments due to their small size, we used super-resolution microscopy. Methods: Mouse primary hippocampal neurons were immunolabelled and imaged by stimulated emission depletion (STED) microscopy, including three-dimensional, three-channel imaging and image analyses. Results: The first (β-secretase) and second (γ-secretase) cleavages of AβPP were localized to functionally and distally distinct compartments. The β-secretase cleavage was observed in early endosomes, where we were able to show that the liberated N- and C-terminal fragments were sorted into distinct vesicles budding from the early endosomes in soma. Lack of colocalization of Aβ 42 and APP-CTF in soma suggested that γ-secretase cleavage occurs in neurites. Indeed, APP-CTF was, in line with Aβ 42 in our previous study, enriched in the presynapse but absent from the postsynapse. In contrast, full-length AβPP was not detected in either the pre- or the postsynaptic side of the synapse. Furthermore, we observed that endogenously produced and endocytosed Aβ 42 were localized in different compartments. Conclusion: These findings provide critical super-resolved insight into amyloidogenic AβPP processing in primary neurons.

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A theoretical study on the molecular determinants of the affibody protein ZAβ3bound to an amyloid β peptide

Physical Chemistry Chemical Physics ◽

10.1039/c5cp00615e ◽

2015 ◽

Vol 17 (26) ◽

pp. 16886-16893 ◽

Cited By ~ 3

Author(s):

Xu Wang ◽

Xianqiang Sun ◽

Guanglin Kuang ◽

Hans Ågren ◽

Yaoquan Tu

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Theoretical Study ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Aβ Peptides ◽

Molecular Determinants

The investigation of the (ZAβ3)2:Aβ complex highlights the energetic contribution of affibody residues to the binding with alzheimer's disease associated Aβ peptides.

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Gallium nanoparticles as novel inhibitors of Aβ40 aggregation

Materials Advances ◽

10.1039/d1ma00461a ◽

2021 ◽

Author(s):

Rolando Oyola ◽

Deguo Du ◽

Idalia Ramos ◽

Kyabeth Torres ◽

Ambar S Delgado ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Amyloid Plaques ◽

Aβ Peptides ◽

Gallium Nanoparticles

Alzheimer’s disease (AD) has been consistently related to the formation of senile amyloid plaques mainly composed of amyloid β (Aβ) peptides. The toxicity of Aβ aggregates has been indicated to...

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Implication of exosomes derived from cholesterol-accumulated astrocytes in Alzheimer's disease pathology

Disease Models & Mechanisms ◽

10.1242/dmm.048929 ◽

2021 ◽

Author(s):

Qi Wu ◽

Leonardo Cortez ◽

Razieh Kamali-Jamil ◽

Valerie Sim ◽

Holger Wille ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Influence Function ◽

Critical Role ◽

Amyloid Β ◽

Cholesterol Accumulation ◽

Aβ Peptides ◽

Neuronal Viability ◽

Cultured Astrocytes ◽

Aβ Production

Amyloid β (Aβ) peptides generated from the amyloid precursor protein (APP) play a critical role in the development of Alzheimer's disease (AD) pathology. Aβ-containing neuronal exosomes, which represent a novel form of intercellular communication, have been shown to influence function/vulnerability of neurons in AD. Unlike neurons, the significance of exosomes derived from astrocytes remains unclear. In this study, we evaluated the significance of exosomes derived from U18666A-induced cholesterol-accumulated astrocytes in the development of AD pathology. Our results show that cholesterol accumulation decreases exosome secretion, whereas lowering cholesterol level increases exosome secretion from cultured astrocytes. Interestingly, exosomes secreted from U18666A-treated astrocytes contain higher levels of APP, APP-CTFs, soluble APP, APP secretases and Aβ1-40 than exosomes secreted from control astrocytes. Furthermore, we show that exosomes derived from U18666A-treated astrocytes can lead to neurodegeneration, which is attenuated by decreasing Aβ production or by neutralizing exosomal Aβ peptide with an Aβ antibody. These results, taken together, suggest that exosomes derived from cholesterol-accumulated astrocytes can play an important role in trafficking APP/Aβ peptides and influencing neuronal viability in the affected regions of the AD brain.

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Copper Binding to the Amyloid-β (Aβ) Peptide Associated with Alzheimer's Disease

Journal of Biological Chemistry ◽

10.1074/jbc.m313572200 ◽

2004 ◽

Vol 279 (18) ◽

pp. 18169-18177 ◽

Cited By ~ 315

Author(s):

Christopher D. Syme ◽

Rebecca C. Nadal ◽

Stephen E. J. Rigby ◽

John H. Viles

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Aβ Peptide ◽

Copper Binding

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Enhancing α-secretase Processing for Alzheimer’s Disease—A View on SFRP1

Brain Sciences ◽

10.3390/brainsci10020122 ◽

2020 ◽

Vol 10 (2) ◽

pp. 122 ◽

Cited By ~ 1

Author(s):

Bor Luen Tang

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Experimental Therapeutics ◽

Related Protein ◽

Endogenous Inhibitor ◽

Aβ Peptides ◽

App Processing ◽

Promising Therapeutic Target ◽

A Disintegrin And Metalloproteinase

Amyloid β (Aβ) peptides generated via sequential β- and γ-secretase processing of the amyloid precursor protein (APP) are major etiopathological agents of Alzheimer’s disease (AD). However, an initial APP cleavage by an α-secretase, such as the a disintegrin and metalloproteinase domain-containing protein ADAM10, precludes β-secretase cleavage and leads to APP processing that does not produce Aβ. The latter appears to underlie the disease symptom-attenuating effects of a multitude of experimental therapeutics in AD animal models. Recent work has indicated that an endogenous inhibitor of ADAM10, secreted-frizzled-related protein 1 (SFRP1), is elevated in human AD brains and associated with amyloid plaques in mouse AD models. Importantly, genetic or functional attenuation of SFRP1 lowered Aβ accumulation and improved AD-related histopathological and neurological traits. Given SFRP1′s well-known activity in attenuating Wnt signaling, which is also commonly impaired in AD, SFRP1 appears to be a promising therapeutic target for AD. This idea, however, needs to be addressed with care because of cancer enhancement potentials resulting from a systemic loss of SFRP1 activity, as well as an upregulation of ADAM10 activity. In this focused review, I shall discuss α-secretase-effected APP processing in AD with a focus on SFRP1, and explore the contrasting perspectives arising from the recent findings.

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Blood-based high sensitivity measurements of beta-amyloid and phosphorylated tau as biomarkers of Alzheimer’s disease: a focused review on recent advances

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2021-327370 ◽

2021 ◽

pp. jnnp-2021-327370

Author(s):

Joyce R. Chong ◽

Nicholas J. Ashton ◽

Thomas K. Karikari ◽

Tomotaka Tanaka ◽

Michael Schöll ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Molecule ◽

Emerging Technologies ◽

Amyloid Β ◽

High Sensitivity ◽

Phosphorylated Tau ◽

Meso Scale Discovery ◽

Aβ Peptides

Discovery and development of clinically useful biomarkers for Alzheimer’s disease (AD) and related dementias have been the focus of recent research efforts. While cerebrospinal fluid and positron emission tomography or MRI-based neuroimaging markers have made the in vivo detection of AD pathology and its consequences possible, the high cost and invasiveness have limited their widespread use in the clinical setting. On the other hand, advances in potentially more accessible blood-based biomarkers had been impeded by lack of sensitivity in detecting changes in markers of the hallmarks of AD, including amyloid-β (Aβ) peptides and phosphorylated tau (P-tau). More recently, however, emerging technologies with superior sensitivity and specificity for measuring Aβ and P-tau have reported high concordances with AD severity. In this focused review, we describe several emerging technologies, including immunoprecipitation-mass spectrometry (IP-MS), single molecule array and Meso Scale Discovery immunoassay platforms, and appraise the current literature arising from their use to identify plaques, tangles and other AD-associated pathology. While there is potential clinical utility in adopting these technologies, we also highlight the further studies needed to establish Aβ and P-tau as blood-based biomarkers for AD, including validation with existing large sample sets, new independent cohorts from diverse backgrounds as well as population-based longitudinal studies. In conclusion, the availability of sensitive and reliable measurements of Aβ peptides and P-tau species in blood holds promise for the diagnosis, prognosis and outcome assessments in clinical trials for AD.

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