bims-proned 2024-05-12 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2024–05–12
seventeen papers selected by
Verena Kohler, Umeå University

Pharmacological inhibition of α-synuclein aggregation within liquid condensates.
Molecular docking analysis of α-Synuclein aggregation with Anle138b.
The misfolding mystery: α-syn and the pathogenesis of Parkinson's disease.
Modulating α-synuclein propagation and decomposition: implications in Parkinson's disease therapy.
4-Oxo-2-Nonenal- and Agitation-Induced Aggregates of α-Synuclein and Phosphorylated α-Synuclein with Distinct Biophysical Properties and Biomedical Applications.
An NMR Toolkit to Probe Amyloid Oligomer Inhibition in Neurodegenerative Diseases: From Ligand Screening to Dissecting Binding Topology and Mechanisms of Action.
2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.
Rationally Designed Peptoid Inhibitors of Amyloid-β Oligomerization.
Synapsin E-domain is essential for α-synuclein function.
Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and in vitro inhibition of amyloid β1-42 peptide aggregation, acetylcholinesterase and carbonic anhydrase-II.
Super-Resolution Imaging Uncovers Nanoscale Tau Aggregate Hyperphosphorylation Patterns in Human Alzheimer's Disease Brain Tissue.
Linalool acts as a chemical chaperone by inhibiting amyloid-β aggregation.
The αSynuclein half-life conundrum.
Accelerating protein aggregation and amyloid fibrillation for rapid inhibitor screening.
ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus.
Editorial: Promising therapeutic strategies for Alzheimer's disease: a focus on amyloid-β targeting.
Characterizing the oligomers distribution along the aggregation pathway of amyloid Aß1-40 by NMR.

Nat Commun. 2024 May 07. 15(1): 3835

Pharmacological inhibition of α-synuclein aggregation within liquid condensates.

Samuel T Dada, Zenon Toprakcioglu, Mariana P Cali, Alexander Röntgen, Maarten C Hardenberg, Owen M Morris, Lena K Mrugalla, Tuomas P J Knowles, Michele Vendruscolo.

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson's disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson's disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson's disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

DOI: https://doi.org/10.1038/s41467-024-47585-x
Bioinformation. 2024 ;20(3): 217-222

Molecular docking analysis of α-Synuclein aggregation with Anle138b.

Annu Grewal, Deepak Sheokand, Vandana Saini, Ajit Kumar.

  α-Synuclein aggregation into toxic oligomeric species is central to Parkinson's disease pathogenesis. Anle138b is a recently identified inhibitor of α-synuclein oligomerization showing promise in preclinical studies. This study employed computational approaches to elucidate Anle138b's mechanism of oligomer-specific action. The inhibitory potential of Anle138b against α-synuclein oligomers was evaluated by performing molecular docking studies using AutoDock Tools, followed by their binding pocket analysis. Further, protein-protein docking studies were performed using Hex8.0 to validate the aggregation inhibitory potential of Anle138b. Molecular docking revealed increasing binding affinity of Anle138b against higher order α-synuclein oligomers (dimer to decamer). Anle138b occupied oligomeric cavity and interacted with residues Thr54, Gly73, Val74 and Thr75 across several oligomers. Protein-protein docking showed that Anle138b interferes with α-synuclein decamer formation. These results highlight the oligomer-directed inhibitory mechanism of Anle138b, without hindering the monomeric forms and provide molecular insights to advance its therapeutic development for Parkinson's and related synucleinopathies.

Keywords:  Molecular docking; Parkinson's disease; protein-protein docking; α-synuclein aggregation

DOI:  https://doi.org/10.6026/973206300200217
Neurochem Int. 2024 May 07. pii: S0197-0186(24)00087-1. [Epub ahead of print]177 105760

The misfolding mystery: α-syn and the pathogenesis of Parkinson's disease.

Samir Negi, Navneet Khurana, Navneet Duggal.

Neurodegenerative diseases such as Parkinson's disease (PD) are characterized by the death of neurons in specific areas of the brain. One of the proteins that is involved in the pathogenesis of PD is α-syn (α-syn). α-Syn is a normal protein that is found in all neurons, but in PD, it misfolds and aggregates into toxic fibrils. These fibrils can then coalesce into pathological inclusions, such as Lewy bodies and Lewy neurites. The pathogenic pathway of PD is thought to involve a number of steps, including misfolding and aggregation of α-syn, mitochondrial dysfunction, protein clearance impairment, neuroinflammation and oxidative stress. A deeper insight into the structure of α-syn and its fibrils could aid in understanding the disease's etiology. The prion-like nature of α-syn is also an important area of research. Prions are misfolded proteins that can spread from cell to cell, causing other proteins to misfold as well. It is possible that α-syn may behave in a similar way, spreading from cell to cell and causing a cascade of misfolding and aggregation. Various post-translational alterations have also been observed to play a role in the pathogenesis of PD. These alterations can involve a variety of nuclear and extranuclear activities, and they can lead to the misfolding and aggregation of α-syn. A better understanding of the pathogenic pathway of PD could lead to the development of new therapies for the treatment of this disease.

DOI: https://doi.org/10.1016/j.neuint.2024.105760
Ageing Res Rev. 2024 May 06. pii: S1568-1637(24)00137-5. [Epub ahead of print] 102319

Modulating α-synuclein propagation and decomposition: implications in Parkinson's disease therapy.

Beining Li, Xue Xiao, Mingxia Bi, Qian Jiao, Xi Chen, Chunling Yan, Xixun Du, Hong Jiang.

  α-Synuclein (α-Syn) is closely related to the pathogenesis of Parkinson's disease (PD). Under pathological conditions, the conformation of α-syn changes and different forms of α-syn lead to neurotoxicity. According to Braak stages, α-syn can propagate in different brain regions, inducing neurodegeneration and corresponding clinical manifestations through abnormal aggregation of Lewy bodies (LBs) and lewy axons in different types of neurons in PD. So far, PD lacks early diagnosis biomarkers, and treatments are mainly targeted at some clinical symptoms. There is no effective therapy to delay the progression of PD. This review first summarized the role of α-syn in physiological and pathological states, and the relationship between α-syn and PD. Then, we focused on the origin, secretion, aggregation, propagation and degradation of α-syn as well as the important regulatory factors in these processes systematically. Finally, we reviewed some potential drug candidates for alleviating the abnormal aggregation of α-syn in order to provide valuable targets for the treatment of PD to cope with the occurrence and progression of this disease.

Keywords:  Parkinson's disease; decomposition; propagation; α-synuclein fibrils; α-synuclein oligomers

DOI:  https://doi.org/10.1016/j.arr.2024.102319
Cells. 2024 Apr 24. pii: 739. [Epub ahead of print]13(9):

4-Oxo-2-Nonenal- and Agitation-Induced Aggregates of α-Synuclein and Phosphorylated α-Synuclein with Distinct Biophysical Properties and Biomedical Applications.

Tie Wang, Weijin Liu, Qidi Zhang, Jie Jiao, Zihao Wang, Ge Gao, Hui Yang.

  α-Synuclein (α-syn) can form oligomers, protofibrils, and fibrils, which are associated with the pathogenesis of Parkinson's disease and other synucleinopathies. Both the lipid peroxidation product 4-oxo-2-nonenal (ONE) and agitation can induce aggregation of α-syn and phosphorylated α-syn. Thus, clarification of the characteristics of different α-syn species could help to select suitable aggregates for diagnosis and elucidate the pathogenesis of diseases. Here, we characterized ONE-induced wild-type (WT) α-syn aggregates (OW), ONE-induced phosphorylated α-syn (p-α-syn) aggregates (OP), agitation-induced α-syn preformed fibrils (PFF), and agitation-induced p-α-syn preformed fibrils (pPFF). Thioflavin T (ThT) dying demonstrated that OW and OP had fewer fibrils than the PFF and pPFF. Transmission electron microscopy revealed that the lengths of PFF and pPFF were similar, but the diameters differed. OW and OP had more compact structures than PFF and pPFF. Aggregation of p-α-syn was significantly faster than WT α-syn. Furthermore, OW and OP were more sodium dodecyl sulfate-stable and proteinase K-resistant, suggesting greater stability and compactness, while aggregates of PFF and pPFF were more sensitive to proteinase K treatment. Both ONE- and agitation-induced aggregates were cytotoxic when added exogenously to SH-SY5Y cells with increasing incubation times, but the agitation-induced aggregates caused cell toxicity in a shorter time and more p-α-syn inclusions. Similarly, p-proteins were more cytotoxic than non-p-proteins. Finally, all four aggregates were used as standard antigens to establish sandwich enzyme-linked immunosorbent assay (ELISA). The results showed that the recognition efficiency of OW and OP was more sensitive than that of PFF and pPFF. The OW- and OP-specific ELISA for detection of p-α-syn and α-syn in plasma samples of Thy1-α-syn transgenic mice showed that the content of aggregates could reflect the extent of disease. ONE and agitation induced the formation of α-syn aggregates with distinct biophysical properties and biomedical applications.

Keywords:  4-oxo-2-nonenal (ONE); aggregates; enzyme-linked immunosorbent assay; phosphorylation; preformed fibrils (PFF); α-synuclein

DOI:  https://doi.org/10.3390/cells13090739
Chempluschem. 2024 May 07. e202400243

An NMR Toolkit to Probe Amyloid Oligomer Inhibition in Neurodegenerative Diseases: From Ligand Screening to Dissecting Binding Topology and Mechanisms of Action.

Alessandro Palmioli, Cristina Airoldi.

  The aggregation of amyloid peptides and proteins into toxic oligomers is a hallmark of neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Inhibition of amyloid oligomers formation and interactions with biological counterparts, as well as the triggering of non-toxic amorphous aggregates, are strategies towards preventive interventions against these pathologies. NMR spectroscopy addresses the need for structural characterization of amyloid proteins and their aggregates, their binding to inhibitors, and rapid screening of compound libraries for ligand identification. Here we briefly discuss the solution experiments constituting the NMR spectroscopist's toolkit and provide examples of their application.

Keywords:  NMR spectroscopy, molecular recognition, neurodegenerative diseases, amyloid aggregates, amyloid inhibitors

DOI:  https://doi.org/10.1002/cplu.202400243
ACS Chem Neurosci. 2024 May 10.

2-Butoxytetrahydrofuran, Isolated from Holothuria scabra, Attenuates Aggregative and Oxidative Properties of α-Synuclein and Alleviates Its Toxicity in a Transgenic Caenorhabditis elegans Model of Parkinson's Disease.

Sukrit Promtang, Tanatcha Sanguanphun, Pawanrat Chalorak, Laurence S Pe, Nakorn Niamnont, Prasert Sobhon, Krai Meemon.

  Aggregative α-synuclein and incurring oxidative stress are pivotal cascading events, leading to dopaminergic (DAergic) neuronal loss and contributing to clinical manifestations of Parkinson's disease (PD). Our previous study demonstrated that 2-butoxytetrahydrofuran (2-BTHF), isolated from Holothuria scabra (H. scabra), could inhibit amyloid-β aggregation and its ensuing toxicity, which leads to Alzheimer's disease. In the present study, we found that 2-BTHF also attenuated the aggregative and oxidative activities of α-synuclein and lessened its toxicity in a transgenic Caenorhabditis elegans (C. elegans) PD model. Such worms treated with 100 μM of 2-BTHF showed substantial reductions in α-synuclein accumulation and DAergic neurodegeneration. Mechanistically, 2-BTHF, at this concentration, significantly decreased aggregation of monomeric α-synuclein and restored locomotion and dopamine-dependent behaviors. Molecular docking exhibited potential bindings of 2-BTHF to HSF-1 and DAF-16 transcription factors. Additionally, 2-BTHF significantly increased the mRNA transcripts of genes encoding proteins involved in proteostasis, including the molecular chaperones hsp-16.2 and hsp-16.49, the ubiquitination/SUMOylation-related ubc-9 gene, and the autophagy-related genes atg-7 and lgg-1. Transcriptomic profiling revealed an additional mechanism of 2-BTHF in α-synuclein-expressing worms, which showed upregulation of PPAR signaling cascades that mediated fatty acid metabolism. 2-BTHF significantly restored lipid deposition, upregulated the fat-7 gene, and enhanced gcs-1-mediated glutathione synthesis in the C. elegans PD model. Taken together, this study demonstrated that 2-BTHF could abrogate aggregative and oxidative properties of α-synuclein and attenuate its toxicity, thus providing a possible therapeutic application for the treatment of α-synuclein-induced PD.

Keywords:  2-butoxytetrahydrofuran; C. elegans; Holothuria scabra; antiaggregation; antioxidation; α-synuclein toxicity

DOI:  https://doi.org/10.1021/acschemneuro.4c00008
Chembiochem. 2024 May 07. e202400060

Rationally Designed Peptoid Inhibitors of Amyloid-β Oligomerization.

Mihyun Lim Waugh, Lauren Wolf, Kelly Moore, Shannon Servoss, Melissa Moss.

  While plaques comprised of fibrillar Aβ aggregates are hallmarks of Alzheimer's disease, soluble Aβ oligomers present higher neurotoxicity. Thus, one therapeutic approach is to prevent the formation of Aβ oligomers and reduce their associated harmful effects. We have proposed a peptoid mimic of the Aβ hydrophobic KLVFF core as an ideal candidate aggregation inhibitor due to its ability to evade proteolytic degradation via repositioning of the side chain from the α-carbon to the amide nitrogen. This peptoid, JPT1, utilizes chiral sidechains to achieve a helical structure, while C-terminal addition of two phenylalanine residues places aromatic groups on two sides of the helix with spacing designed to facilitate interaction with amyloid β-sheet structure. We have previously shown that JPT1 modulates Aβ fibril formation. Here, we demonstrate that JPT1 also modulates Aβ oligomerization, and we explore the role of the charge on the linker between the KLVFF mimic and the extended aromatic residues. Additionally, we demonstrate that peptoid-induced changes in Aβ oligomerization correlate with attenuation of oligomer-induced nuclear factor-κB activation in SH-SY5Y human neuroblastoma cells. These findings support the therapeutic potential of peptoids to target early stages of Aβ aggregation and impact the associated Aβ-induced cellular response.

Keywords:  Alzheimer's disease; aggregation; amyloid-beta peptides; oligomerization; peptoid

DOI:  https://doi.org/10.1002/cbic.202400060
Elife. 2024 May 07. pii: RP89687. [Epub ahead of print]12

Synapsin E-domain is essential for α-synuclein function.

Alexandra Stavsky, Leonardo A Parra-Rivas, Shani Tal, Jen Riba, Kayalvizhi Madhivanan, Subhojit Roy, Daniel Gitler.

  The cytosolic proteins synucleins and synapsins are thought to play cooperative roles in regulating synaptic vesicle (SV) recycling, but mechanistic insight is lacking. Here, we identify the synapsin E-domain as an essential functional binding-partner of α-synuclein (α-syn). Synapsin E-domain allows α-syn functionality, binds to α-syn, and is necessary and sufficient for enabling effects of α-syn at synapses of cultured mouse hippocampal neurons. Together with previous studies implicating the E-domain in clustering SVs, our experiments advocate a cooperative role for these two proteins in maintaining physiologic SV clusters.

Keywords:  alpha-synuclein; cell biology; mouse; neuroscience; presynaptic; synapsin; synaptic terminals; synaptic transmission; synaptic vesicles

DOI:  https://doi.org/10.7554/eLife.89687
RSC Adv. 2024 May 02. 14(21): 14742-14757

Pregnenolone derivatives for the treatment of Alzheimer's disease: synthesis, and in vitro inhibition of amyloid β1-42 peptide aggregation, acetylcholinesterase and carbonic anhydrase-II.

Ayesha Tahir, Bushra Mobeen, Fahad Hussain, Abdul Sadiq, Umer Rashid.

The amyloid state, which is a specific conformation of proteins, offers valuable information about both functional protein structures and the pathological assemblies associated with various diseases. One of the major hallmarks of Alzheimer's disease includes primarily the extracellular build-up of a peptide known as amyloid-β, which has a sequence consisting of 39 to 42 amino acid residues, and the formation of intracellular neurofibrillary tangles mostly consisting of hyperphosphorylated tau protein. Drugs that are expected to reduce Aβ production, prevent Aβ aggregation, and promote Aβ clearance are promising approaches for treating AD. Current work is focused on identifying the compounds that have balanced even mild biological activities against multiple targets instead of finding one-target compound with high potency. We synthesized pregnenolone derivatives and evaluated their potential against inhibition of eeAChE/eqBChE, hCA-II and self-mediated Aβ1-42 peptide aggregation. Our synthesized derivatives 23, and 25-27 exhibited concomitant inhibition of all the tested macromolecular targets. All the active compounds were found to be BBB penetrants in the PAMPA assay. Furthermore, these selected compounds were found to be non-neurotoxic in the MTT assay on neuroblastoma SH-SY5Y cells. Docking studies support dual binding site (PAS and CAS) inhibition of AChE which showed Aβ1-42 aggregation and AChE inhibition. Moreover, docking studies carried out on the 3D crystallographic structure of Aβ1-42 peptide (PDB ID = 1IYT) showed significant interactions with amino acid residues Asp 23 and Lys 28, and hydrophobic interactions with the Phe19, Phe20, and Ala 30 effectively impeding the formation of β-sheet structures.

DOI: https://doi.org/10.1039/d4ra01536c
bioRxiv. 2024 Apr 25. pii: 2024.04.24.590893. [Epub ahead of print]

Super-Resolution Imaging Uncovers Nanoscale Tau Aggregate Hyperphosphorylation Patterns in Human Alzheimer's Disease Brain Tissue.

Adriana N Santiago-Ruiz, Siewert Hugelier, Charles R Bond, Edward B Lee, Melike Lakadamyali.

Tau aggregation plays a critical role in Alzheimer's Disease (AD), where tau neurofibrillary tangles (NFTs) are a key pathological hallmark. While much attention has been given to NFTs, emerging evidence underscores nano-sized pre-NFT tau aggregates as potentially toxic entities in AD. By leveraging DNA-PAINT super-resolution microscopy, we visualized and quantified nanoscale tau aggregates (nano-aggregates) in human postmortem brain tissues from intermediate and advanced AD, and Primary Age-Related Tauopathy (PART). Nano-aggregates were predominant across cases, with AD exhibiting a higher burden compared to PART. Hyperphosphorylated tau residues (p-T231, p-T181, and p-S202/T205) were present within nano-aggregates across all AD Braak stages and PART. Moreover, nano-aggregates displayed morphological differences between PART and AD, and exhibited distinct hyperphosphorylation patterns in advanced AD. These findings suggest that changes in nano-aggregate morphology and hyperphosphorylation patterns may exacerbate tau aggregation and AD progression. The ability to detect and profile nanoscale tau aggregates in human brain tissue opens new avenues for studying the molecular underpinnings of tauopathies.

DOI: https://doi.org/10.1101/2024.04.24.590893
Neurochem Int. 2024 May 07. pii: S0197-0186(24)00089-5. [Epub ahead of print] 105762

Linalool acts as a chemical chaperone by inhibiting amyloid-β aggregation.

Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur.

  Linalool is a neuroprotective monoterpene found in essential oils from aromatic plants. Linalool's effectiveness in AD animal models has been established previously, but its mechanisms of action remain unclear. Therefore, this study aims to investigate whether linalool binds directly to the amyloid beta (Aβ) fibrils to understand it's role in preventing neurodegeneration. The anti-aggregation ability of Linalool was determined using Dithiothreitol (DTT), and thermal aggregation assays followed by Thioflavin T (ThT) binding assay. AD animals were treated with Linalool, and Thioflavin T staining was used to check the binding of linalool to Aβ fibrils in rat brain tissue sections. Preliminary studies revealed the anti-aggregation potential of linalool under the thermal and chemical stimulus. Further, in ThT binding assay Linalool inhibited Aβ aggregation, binding directly to Aβ fibrils. The reduced fluorescence intensity of ThT in AD brain tissues following linalool administration, highlights its neuroprotective potential as a therapeutic agent for AD.

Keywords:  Alzheimer’s disease; Chaperone; Natural compound; Neuroprotective effect; β-amyloid fibrils

DOI:  https://doi.org/10.1016/j.neuint.2024.105762
Neurobiol Dis. 2024 May 04. pii: S0969-9961(24)00123-2. [Epub ahead of print]196 106524

The αSynuclein half-life conundrum.

Anna Masato, Luigi Bubacco.

  αSynuclein (αSyn) misfolding and aggregation frequently precedes neuronal loss associated with Parkinson's Disease (PD) and other Synucleinopathies. The progressive buildup of pathological αSyn species results from alterations on αSyn gene and protein sequence, increased local concentrations, variations in αSyn interactome and protein network. Therefore, under physiological conditions, it is mandatory to regulate αSyn proteostasis as an equilibrium among synthesis, trafficking, degradation and extracellular release. In this frame, a crucial parameter is protein half-life. It provides indications of the turnover of a specific protein and depends on mRNA synthesis and translation regulation, subcellular localization, function and clearance by the designated degradative pathways. For αSyn, the molecular mechanisms regulating its proteostasis in neurons have been extensively investigated in various cellular models, either using biochemical or imaging approaches. Nevertheless, a converging estimate of αSyn half-life has not emerged yet. Here, we discuss the challenges in studying αSyn proteostasis under physiological and pathological conditions, the advantages and disadvantages of the experimental strategies proposed so far, and the relevance of determining αSyn half-life from a translational perspective.

Keywords:  Biomarker; Protein half-life; Proteostasis; αSynuclein

DOI:  https://doi.org/10.1016/j.nbd.2024.106524
Chem Sci. 2024 May 08. 15(18): 6853-6859

Accelerating protein aggregation and amyloid fibrillation for rapid inhibitor screening.

Jingjin Fan, Liwen Liang, Xiaoyu Zhou, Zheng Ouyang.

The accumulation and deposition of amyloid fibrils, also known as amyloidosis, in tissues and organs of patients has been found to be linked to numerous devastating neurodegenerative diseases. The aggregation of proteins to form amyloid fibrils, however, is a slow pathogenic process, and is a major issue for the evaluation of the effectiveness of inhibitors in new drug discovery and screening. Here, we used microdroplet reaction technology to accelerate the amyloid fibrillation process, monitored the process to shed light on the fundamental mechanism of amyloid self-assembly, and demonstrated the value of the technology in the rapid screening of potential inhibitor drugs. Proteins in microdroplets accelerated to form fibrils in milliseconds, enabling an entire cycle of inhibitor screening for Aβ40 within 3 minutes. The technology would be of broad interest to drug discovery and therapeutic design to develop treatments for diseases associated with protein aggregation and fibrillation.

DOI: https://doi.org/10.1039/d4sc00437j
bioRxiv. 2024 Apr 22. pii: 2024.04.18.590133. [Epub ahead of print]

ProSAAS is Preferentially Secreted from Neurons During Homeostatic Scaling and Reduces Amyloid Plaque Size in the 5xFAD Mouse Hippocampus.

Samira Mitias, Nicholas Schaffer, Saaya Nair, Chelsea Hook, Iris Lindberg.

The accumulation of β-amyloid in Alzheimer's disease greatly impacts neuronal health and synaptic function. To maintain network stability in the face of altered synaptic activity, neurons engage a feedback mechanism termed homeostatic scaling; however, this process is thought to be disrupted during disease progression. Previous proteomics studies have shown that one of the most highly regulated proteins in cell culture models of homeostatic scaling is the small secretory chaperone proSAAS. Our prior work has shown that proSAAS exhibits anti-aggregant behavior against alpha synuclein and β-amyloid fibrillation in vitro , and is upregulated in cell models of proteostatic stress. However, the specific role that this protein might play in homeostatic scaling, and its anti-aggregant role in Alzheimer's progression, is not clear. To learn more about the role of proSAAS in maintaining hippocampal proteostasis, we compared its expression in a primary neuron model of homeostatic scaling to other synaptic components using Western blotting and qPCR, revealing that proSAAS protein responses to homeostatic up- and down-regulation were significantly higher than those of two other synaptic vesicle components, 7B2 and carboxypeptidase E. However, proSAAS mRNA expression was static, suggesting translational control (and/or reduced degradation). ProSAAS was readily released upon depolarization of differentiated hippocampal cultures, supporting its synaptic localization. Immunohistochemical analysis demonstrated abundant proSAAS within the mossy fiber layer of the hippocampus in both wild-type and 5xFAD mice; in the latter, proSAAS was also concentrated around amyloid plaques. Interestingly, overexpression of proSAAS in the CA1 region via stereotaxic injection of proSAAS-encoding AAV2/1 significantly decreased amyloid plaque burden in 5xFAD mice. We hypothesize that dynamic changes in proSAAS expression play a critical role in hippocampal proteostatic processes, both in the context of normal homeostatic plasticity and in the control of protein aggregation during Alzheimer's disease progression.

DOI: https://doi.org/10.1101/2024.04.18.590133
Front Neurosci. 2024 ;18 1415641

Editorial: Promising therapeutic strategies for Alzheimer's disease: a focus on amyloid-β targeting.

Alessandra Bigi, Ryan Limbocker, Cristina Cecchi.



Keywords:  NMDA—receptor; amyloid aggregation; inflammation; memantine; neurodegeneration; neurotoxicity; tauroursodeoxycholic acid

DOI:  https://doi.org/10.3389/fnins.2024.1415641
Chemistry. 2024 May 07. e202400594

Characterizing the oligomers distribution along the aggregation pathway of amyloid Aß1-40 by NMR.

Katiuscia Pagano, Lucia De Rosa, Simona Tomaselli, Henriette Molinari, Luca Domenico D'Andrea, Laura Ragona.

  This study delves into the early aggregation process of the Aβ1-40 amyloid peptide, elucidating the associated oligomers distribution. Motivated by the acknowledged role of small oligomers in the neurotoxic damage linked to Alzheimer's disease, we present an experimental protocol for preparing 26-O-acyl isoAβ1-40, a modified Aβ1-40 peptide facilitating rapid isomerization to the native amide form at neutral pH. This ensures seed-free solutions, minimizing experimental variability. Additionally, we demonstrate the efficacy of coupling NMR diffusion ordered spectroscopy (DOSY) with the Inverse Laplace Transform (ILT) reconstruction method, for effective characterization of early aggregation processes. This innovative approach efficiently maps oligomers distributions across a wide spectrum of initial peptide concentrations offering unique insights into the evolution of oligomers relative populations. As a proof of concept, we demonstrate the efficacy of our approach assessing the impact of Epigallocathechin gallate, a known remodeling agent of amyloid fibrils, on the oligomeric distributions of aggregated Aß1-40. The DOSY-ILT proposed approach stands as a robust and discriminating asset, providing a powerful strategy for rapidly gaining insight into potential inhibitors' impact on the aggregation process.

Keywords:  NMR; amyloid-β; depsi-peptide; diffusion ordered spectroscopy; oligomers

DOI:  https://doi.org/10.1002/chem.202400594