aβ42 peptide
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Biomolecules ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 1818
Author(s):  
Sang-Heon Kim ◽  
Eun-Hye Lee ◽  
Hyung-Ji Kim ◽  
A-Ru Kim ◽  
Ye-Eun Kim ◽  
...  

Alzheimer’s disease (AD) is a degenerative brain disease that is the most common cause of dementia. The incidence of AD is rapidly rising because of the aging of the world population. Because AD is presently incurable, early diagnosis is very important. The disease is characterized by pathological changes such as deposition of senile plaques and decreased concentration of the amyloid-beta 42 (Aβ42) peptide in the cerebrospinal fluid (CSF). The concentration of Aβ42 in the CSF is a well-studied AD biomarker. The specific peptide probe was screened through four rounds of biopanning, which included the phage display process. The screened peptide showed strong binding affinity in the micromolar range, and the enzyme-linked peptide assay was optimized using the peptide we developed. This diagnostic method showed specificity toward Aβ42 in the presence of other proteins. The peptide-binding site was also estimated using molecular docking analysis. Finally, the diagnostic method we developed could significantly distinguish patients who were classified based on amyloid PET images.


2021 ◽  
Author(s):  
Thomas Löhr ◽  
Kai Kohlhoff ◽  
Gabriella T. Heller ◽  
Carlo Camilloni ◽  
Michele Vendruscolo

The stabilisation of native states of proteins is a powerful drug discovery strategy. It is still unclear, however, whether this approach can be applied to intrinsically disordered proteins. Here we report a small molecule that stabilises the native state of the Aβ42 peptide, an intrinsically disordered protein fragment associated with Alzheimer's disease. We show that this stabilisation takes place by a dynamic binding mechanism, in which both the small molecule and the Aβ42 peptide remain disordered. This disordered binding mechanism involves enthalpically favourable local π-stacking interactions coupled with entropically advantageous global effects. These results indicate that small molecules can stabilise disordered proteins in their native states through transient non-specific interactions that provide enthalpic gain while simultaneously increasing the conformational entropy of the proteins.


2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Inmaculada Cuchillo-Ibañez ◽  
Matthew P. Lennol ◽  
Sergio Escamilla ◽  
Trinidad Mata-Balaguer ◽  
Lucía Valverde-Vozmediano ◽  
...  

Abstract Background Members of the low-density lipoprotein (LDL) receptor family are involved in endocytosis and in transducing signals, but also in amyloid precursor protein (APP) processing and β-amyloid secretion. ApoER2/LRP8 is a member of this family with key roles in synaptic plasticity in the adult brain. ApoER2 is cleaved after the binding of its ligand, the reelin protein, generating an intracellular domain (ApoER2-ICD) that modulates reelin gene transcription itself. We have analyzed whether ApoER2-ICD is able to regulate the expression of other LDL receptors, and we focused on LRP3, the most unknown member of this family. We analyzed LRP3 expression in middle-aged individuals (MA) and in cases with Alzheimer’s disease (AD)-related pathology, and the relation of LRP3 with APP. Methods The effects of full-length ApoER2 and ApoER2-ICD overexpression on protein levels, in the presence of recombinant reelin or Aβ42 peptide, were evaluated by microarray, qRT-PCRs, and western blots in SH-SY5Y cells. LRP3 expression was analyzed in human frontal cortex extracts from MA subjects (mean age 51.8±4.8 years) and AD-related pathology subjects [Braak neurofibrillary tangle stages I–II, 68.4±8.8 years; III–IV, 80.4 ± 8.8 years; V–VI, 76.5±9.7 years] by qRT-PCRs and western blot; LRP3 interaction with other proteins was assessed by immunoprecipitation. In CHO cells overexpressing LRP3, protein levels of full-length APP and fragments were evaluated by western blots. Chloroquine was employed to block the lysosomal/autophagy function. Results We have identified that ApoER2 overexpression increases LRP3 expression, also after reelin stimulation of ApoER2 signaling. The same occurred following ApoER2-ICD overexpression. In extracts from subjects with AD-related pathology, the levels of LRP3 mRNA and protein were lower than those in MA subjects. Interestingly, LRP3 transfection in CHO-PS70 cells induced a decrease of full-length APP levels and APP-CTF, particularly in the membrane fraction. In cell supernatants, levels of APP fragments from the amyloidogenic (sAPPα) or non-amyloidogenic (sAPPβ) pathways, as well as Aβ peptides, were drastically reduced with respect to mock-transfected cells. The inhibitor of lysosomal/autophagy function, chloroquine, significantly increased full-length APP, APP-CTF, and sAPPα levels. Conclusions ApoER2/reelin signaling regulates LRP3 expression, whose levels are affected in AD; LRP3 is involved in the regulation of APP levels.


2021 ◽  
Vol 21 (10) ◽  
pp. 5044-5050
Author(s):  
Yang Xia ◽  
Parasuraman Padmanabhan ◽  
Vimalan Vijayaragavan ◽  
Vadakke Matham Murukeshan ◽  
Balázs Gulyás

One of the most severe diseases threatening the ageing population is Alzheimer’s disease (AD). Recent studies found that the cellular uptake of extracellular amyloid beta (Aβ) peptides can lead to a build-up of intracellular Aβ in certain neuronal cells, which consequently lead to the onset of AD pathogenesis. It is therefore hypothesized that the detection of cells that are involved in such Aβ uptake could facilitate the early diagnosis of AD. In this work, a magnetofluorescent nanoprobe was prepared conjugating dye-labeled Aβ42 peptides with iron oxide nanoparticles (IONPs). When incubated with SH-SY5Y cells, the cellular uptake of Aβ42-IONPs was enhanced, compared to that of bare IONPs. Further, by labelling SH-SY5Y and HCT-116 cells, it was found that the Aβ42-IONPs are selectively targeting the neuronal cells. This enhanced and specific neuronal targeting is attributed to the cellular uptake of extracellular amyloid by SH-SY5Y cells. In addition, the MR relaxivities of the Aβ42-IONPs are preserved after the peptides functionalization. The results suggest that the Aβ42 functionalized magnetofluorescent IONPs can be used as a bimodal probe to interrogate the cellular uptake of amyloid peptides.


2021 ◽  
Vol 55 (2) ◽  
pp. 92-98
Author(s):  
Ismail Ishola ◽  

Background:Neurodegenerative disorders (ND) are characterized by progressive loss of selectively vulnerable populations of neurons, which contrasts with select static neuronal loss. Self-association of amyloid-beta(Aβ)orα-synucleinpeptidesintofibrilsand/orplaquelikeaggregatescauses neurotoxicity. Hence, identification of specific compounds that either inhibit the formation of Aβ or α-syn-fibrils makes an appealing therapeutic strategy in the development of drugs. In the present study, we investigated the protective effect of vildagliptin (VDG) (oral hypoglycemic agent) on genetic models of ND in Drosophila melanogaster. Methods: The disease causing human Aβ42 peptide or α-syn was expressed pan-neuronally (elav-GAL4) or dopamine neurons (DDC-GAL4) using the UAS-GAL4 system. Flies were either grown in food media with or without vildagliptin (1, 5, or 10μM). This was followed by fecundity, larva motility and negative geotaxis assay (climbing) as a measure of neurodegeneration. Results:Elav-Gal4<Aβ flies showed significant decrease in larva contraction and motility indicative of neurodegeneration. However, flies grown on vildaglitptin (VDG) showed dose-dependent and significant increase in larva motility in comparison with flies grown on food media only. Interestingly, the treatments did not affect fecundity when compared with normal food control. Moreover, flies grown on VDG showed no significant change in lifespan. DDC-GAL4<α-syn flies showed significant decrease in larva motility and climbing activity which was ameliorated by supplementation of flies food media with VDG suggestive of neuroprotective activity. Conclusion: Findings from this study showed that vildagliptin is a potential neuroprotective agent in genetic or familial forms of neurodegeneration.


2021 ◽  
Vol 22 (17) ◽  
pp. 9537
Author(s):  
Adela Bernabeu-Zornoza ◽  
Raquel Coronel ◽  
Charlotte Palmer ◽  
Victoria López-Alonso ◽  
Isabel Liste

Amyloid-β 42 peptide (Aβ1-42 (Aβ42)) is well-known for its involvement in the development of Alzheimer’s disease (AD). Aβ42 accumulates and aggregates in fibers that precipitate in the form of plaques in the brain causing toxicity; however, like other forms of Aβ peptide, the role of these peptides remains unclear. Here we analyze and compare the effects of oligomeric and fibrillary Aβ42 peptide on the biology (cell death, proliferative rate, and cell fate specification) of differentiating human neural stem cells (hNS1 cell line). By using the hNS1 cells we found that, at high concentrations, oligomeric and fibrillary Aβ42 peptides provoke apoptotic cellular death and damage of DNA in these cells, but Aβ42 fibrils have the strongest effect. The data also show that both oligomeric and fibrillar Aβ42 peptides decrease cellular proliferation but Aβ42 oligomers have the greatest effect. Finally, both, oligomers and fibrils favor gliogenesis and neurogenesis in hNS1 cells, although, in this case, the effect is more prominent in oligomers. All together the findings of this study may contribute to a better understanding of the molecular mechanisms involved in the pathology of AD and to the development of human neural stem cell-based therapies for AD treatment.


2021 ◽  
Vol 118 (36) ◽  
pp. e2104148118
Author(s):  
Nadejda Koloteva-Levine ◽  
Liam D. Aubrey ◽  
Ricardo Marchante ◽  
Tracey J. Purton ◽  
Jennifer R. Hiscock ◽  
...  

Amyloid seeds are nanometer-sized protein particles that accelerate amyloid assembly as well as propagate and transmit the amyloid protein conformation associated with a wide range of protein misfolding diseases. However, seeded amyloid growth through templated elongation at fibril ends cannot explain the full range of molecular behaviors observed during cross-seeded formation of amyloid by heterologous seeds. Here, we demonstrate that amyloid seeds can accelerate amyloid formation via a surface catalysis mechanism without propagating the specific amyloid conformation associated with the seeds. This type of seeding mechanism is demonstrated through quantitative characterization of the cross-seeded assembly reactions involving two nonhomologous and unrelated proteins: the human Aβ42 peptide and the yeast prion–forming protein Sup35NM. Our results demonstrate experimental approaches to differentiate seeding by templated elongation from nontemplated amyloid seeding and rationalize the molecular mechanism of the cross-seeding phenomenon as a manifestation of the aberrant surface activities presented by amyloid seeds as nanoparticles.


2021 ◽  
pp. mbc.E20-06-0382
Author(s):  
Swetha Gowrishankar ◽  
Lila Lyons ◽  
Nisha Mohd Rafiq ◽  
Agnes Roczniak-Ferguson ◽  
Pietro De Camilli ◽  
...  

The dependence of neurons on microtubule-based motors for the movement of lysosomes over long distances raises questions about adaptations that allow neurons to meet these demands. Recently, JIP3/MAPK8IP3, a neuronally enriched putative adaptor between lysosomes and motors, was identified as a critical regulator of axonal lysosome abundance. In this study, we establish a human induced pluripotent stem cell (iPSC)-derived neuron model for the investigation of axonal lysosome transport and maturation and show that loss of JIP3 results in the accumulation of axonal lysosomes and the Alzheimer's disease-related amyloid precursor protein (APP)-derived Aβ42 peptide. We furthermore reveal an overlapping role of the homologous JIP4 gene in lysosome axonal transport. These results establish a cellular model for investigating the relationship between lysosome axonal transport and amyloidogenic APP processing and more broadly demonstrate the utility of human iPSC-derived neurons for the investigation of neuronal cell biology and pathology. [Media: see text] [Media: see text] [Media: see text] [Media: see text]


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