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Aβ(1-38) interferes with Aβ(1-42) high molecular weight complexes on SDS-PAGE. Different concentrations (in µM) of Aβ(1-38), Aβ(1-40), or Aβ(1-42), either alone or as a mixture were incubated for 24 h and then resolved by gel electrophoresis. A protein ladder is shown in the first lane. Aβ high molecular weight complexes were visualized by standard 15% SDS-PAGE (top panels), while the different starting amounts of Aβ peptides themselves were visualized using an 8 M UREA / 12% SDS-PAGE system (bottom blot). Note that on urea gels, Aβ peptides migrate according to their hydrophobicity and, hence, Aβ(1-38) migrates slower (higher) than Aβ(1-40) or Aβ(1-42).
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The pool of β-Amyloid (Aβ) length variants detected in preclinical and clinical Alzheimer disease (AD) samples suggests a diversity of roles for Aβ peptides. We examined how a naturally occurring variant, e.g. Aβ(1–38), interacts with the AD-related variant, Aβ(1–42), and the predominant physiological variant, Aβ(1–40). Atomic force microscopy, Thi...
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Context 1
... our Western blotting experiments, we used increasing concentrations (2, 10, and 20 µM) to monitor potential aggregation of the various peptides. First, our blots confirm that HFIP-treated Aβ , Aβ(1-40), and Aβ(1-42) preparations contain significant amounts of monomeric species (bottom panels, Fig. 2), as expected 23,24 . In isolation, there are no detectable aggregates in the Aβ or Aβ(1-40) solutions, even at concentrations of 20 µM (top left panel, Fig. 2). In contrast, the 10 and 20 µM solutions of Aβ(1-42) provide evidence of significant high molecular weight (HMW) aggregates. Co-incubation with increasing concentrations of Aβ ...
Context 2
... aggregation of the various peptides. First, our blots confirm that HFIP-treated Aβ , Aβ(1-40), and Aβ(1-42) preparations contain significant amounts of monomeric species (bottom panels, Fig. 2), as expected 23,24 . In isolation, there are no detectable aggregates in the Aβ or Aβ(1-40) solutions, even at concentrations of 20 µM (top left panel, Fig. 2). In contrast, the 10 and 20 µM solutions of Aβ(1-42) provide evidence of significant high molecular weight (HMW) aggregates. Co-incubation with increasing concentrations of Aβ progressively lessens the amount of HMW aggregate associated with 20 µM Aβ(1-42) (top middle and right panels, Fig. 2). Mixtures of Aβ(1-38) and Aβ(1-40) do not ...
Context 3
... even at concentrations of 20 µM (top left panel, Fig. 2). In contrast, the 10 and 20 µM solutions of Aβ(1-42) provide evidence of significant high molecular weight (HMW) aggregates. Co-incubation with increasing concentrations of Aβ progressively lessens the amount of HMW aggregate associated with 20 µM Aβ(1-42) (top middle and right panels, Fig. 2). Mixtures of Aβ(1-38) and Aβ(1-40) do not present any evidence of HMW complexes. These observations confirm that Aβ can interfere with Aβ(1-42) aggregation and, as importantly, suggest that although Aβ(1-38) and Aβ(1-42) aggregates are detected by AFM (see Fig. 1), these aggregates have profoundly different physicochemical properties, ...
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A sensitive and rapid colorimetric biosensor has been developed for determination of amyloid-β peptide (Aβ) and study of amyloidogenesis based on the high peroxidase-like activity of porous bimetallic ZnO-Co3O4 nanocages (NCs). Due to the high binding ability of Aβ monomer to ZnO-Co3O4 NCs, the catalytic activity of ZnO-Co3O4 NCs can be significant...
Citations
... Accelerated fibrillation of Aβ40 indicates that Aβ42 aggregates behave as preformed nuclei, catalyzing the aggregation of Aβ40, despite the low aggregation propensity of Aβ40. Although Aβ40 aggregates are generally less cytotoxic than Aβ42 aggregates (87,88), Aβ40 aggregates would induce the propagation of Aβ self-assembly (including Aβ42, Aβ40, Aβ38, Aβ37) by the elongation or the secondary nucleation process. Thus, the inhibitory effect of Aβ40 on Aβ42 aggregation is limited to the primary nucleation at the initial stage, and rather, Aβ40 participates in the overall aggregation. ...
... Brain levels of soluble Aβ38 are increased in early onset/ familial AD cases and in preclinical amyloidosis (Quartey et al. 2021). In the case of Aβ40, as a blood-based biomarker, it has been described that its higher concentration is associated with a higher risk of developing AD (Seppala et al. 2010;Yang et al. 2020). ...
Alzheimer’s disease (AD) represents the most common type of dementia. A crucial mechanism attributed to its development is amyloid beta (Aβ) dynamics dysregulation. The extent to which exercise can modulate this phenomenon is uncertain. The aim of this study was to summarize the existing literature evaluating this issue. A comprehensive systematic search was performed in Pubmed, Scopus, Embase, Web of Science, and SciELO databases and completed in August 2023, aiming to identify randomized controlled trials investigating the effect of exercise upon Aβ-related pathology. The keywords “exercise” and “amyloid beta”, as well as all their equivalents and similar terms, were used. For the analysis, the negative or positive dementia status of the subjects was initially considered and then the soluble amyloid precursor protein (sAPP) components and Aβ fragments separately. A meta-analysis was performed and involved eight studies (moderate-to-high quality) and 644 assessments, which were 297 for control and 347 for exercise. No overall effect favoring exercise interventions was observed for both negative (SMD95%=0,286 [-0,131; 0,704]; p = 0,179) or positive AD dementia status (SMD95%=0,110 [-0,155; 0,375]; p = 0,416). The absence of an overall effect favoring exercise interventions was also found for Aβ peptides (SMD95%=0,226 [-0,028; 0,480]; p = 0,081) and for sAPP components (SMD95%=-0,038 50 [-0,472; 0,396]; p = 0,863) levels. Our findings suggest that exercise interventions do not improve Aβ-related pathology in both healthy individuals and individuals with dementia (SMD95%=0,157 [-0,059; 0,373]; p = 0,155), indicating that the beneficial effects of exercise for AD reported in previous studies are related to other mechanistic effects rather than direct amyloid effects (PROSPERO registration number: CRD42023426912).
... 3 The retention of Aβ42 plaque in the brain leads to a biochemical decrease in Aβ42 in the cerebrospinal fluid (CSF). 4 The second mechanism of AD is the dysregulation of tau protein phosphorylation, generating insoluble tau protein aggregates in the brain and CSF. 3 Tau protein is a microtubule-associated protein (MAP) with a native predominant unfolded conformation, which usually has a very low tendency toward aggregation and buildup in the intracellular or extracellular space. 5 Hyperphosphorylation and Aβ may potentiate a tendency of tau protein self-aggregation, forming a β-sheet-like structure, further leading to neurofibrillary tangles (NFTs). ...
Typically, Alzheimer's disease (AD) diagnosis is not made at its earliest period, for instance, at mild cognitive impairment (MCI) and early AD (E‐AD). Our study aims to demonstrate a correlation between the screening tools, including the Mini‐Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Clinical Dementia Rating (CDR), and the biological biomarkers in the cerebrospinal fluid (CSF) amyloid beta 1‐42 (Aβ42), phosphorylated tau (p‐tau) proteins and total tau (t‐tau)/Aβ42 ratio in Puerto Ricans > 55 years old with MCI and E‐AD. We evaluated 30 participants, including demographics, memory scales, and CSF biomarkers. Twenty‐eight CSF biomarkers (Aβ42, p‐tau protein, and t‐tau/Aβ42 ratio) were analyzed using the Meso Scale Discovery Platform (MSD). Associations between memory scales (MoCA, MMSE, CDR) and CSF markers were performed using Spearman rho correlation. Our study revealed a statistical association favoring a direct relationship between MMSE and MoCA with t‐tau/Aβ42 ratio in CSF ( P = 0.022, P = 0.035, respectively). We found a trend toward significance with an inverse relationship with MMSE and Aβ42 (P = 0.069) and a direct relationship with MMSE and p‐tau (P = 0.098). MMSE and MoCA screening tests were identified with a statistically significant association with the CSF biomarkers, specifically t‐tau/Aβ42 ratio, in elderly Puerto Ricans with MCI and E‐AD. Puerto Ricans > 55 years old with MCI and E‐AD could be screened confidently with MMSE and MoCA for a higher likelihood of earlier detection and, thus, initiation of disease‐modifying treatment and prompt non‐pharmacological interventions.
... However, due to their inability to penetrate the blood-brain barrier (BBB), most Aβ probes can only be used for the detection of Aβ in vitro [22][23][24]. Therefore, it is of great significance to design Aβ probes that can be used for in vivo imaging [25,26]. In the development of Aβ imaging probes, many luminescent materials stand out because of their excellent photophysical properties, such as curcumin, 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY), etc. (Figure 1) [27]. ...
Alzheimer’s disease (AD) is a neurodegenerative disease. Due to its complex pathological mechanism, its etiology is not yet clear. As one of the main pathological markers of AD, amyloid-β (Aβ) plays an important role in the development of AD. The deposition of Aβ is not only related to the degeneration of neurons, but also can activate a series of pathological events, including the activation of astrocytes and microglia, the breakdown of the blood–brain barrier, and the change in microcirculation, which is the main cause of brain lesions and death in AD patients. Therefore, the development of efficient and reliable Aβ-specific probes is crucial for the early diagnosis and treatment of AD. This paper focuses on reviewing the application of small-molecule fluorescent probes in Aβ imaging in vivo in recent years. These probes efficiently map the presence of Aβ in vivo, providing a pathway for the early diagnosis of AD and providing enlightenment for the design of Aβ-specific probes in the future.
... /fnmol. . the increase of the shorter Aβ37 and Aβ38 could have several beneficial effects, including attenuation of Aβ42-mediated toxicity (Moore et al., 2018;Quartey et al., 2021) and/or reduced Aβ42 aggregation (Nordvall et al., 2018;Braun et al., 2022). These effects would lead to decreased formation of Aβ pathology, and would represent an inverted Aβ pattern to that observed in FAD; see Figure 2. Indeed, higher levels of Aβ38 have been shown to be associated with a lower risk of AD-related changes in clinical studies (Cullen et al., 2022). ...
Recent clinical data with three therapeutic anti-Aβ antibodies have demonstrated that removal of Aβ-amyloid plaques in early Alzheimer's disease (AD) can attenuate disease progression. This ground-breaking progress in AD medicine has validated both the amyloid cascade hypothesis and Aβ-amyloid as therapeutic targets. These results also strongly support therapeutic approaches that aim to reduce the production of amyloidogenic Aβ to prevent the formation of Aβ-pathology. One such strategy, so-called gamma-secretase modulators (GSM), has been thoroughly explored in preclinical settings but has yet to be fully tested in clinical trials. Recent scientific progress has shed new light on the role of Aβ in Alzheimer's disease and suggests that GSMs exhibit specific pharmacological features that hold great promise for the prevention and treatment of Alzheimer's disease. In this short review, we discuss the data that support why it is important to continue to progress in this class of compounds.
... Late-stage AD brains are loaded with Aβ42 peptides that accumulate in a wide range of heterogeneous structures, while Aβ40 peptides are less prone to accumulate [1,2]. The relevance of Aβ38 peptides is less clear and they may play context-dependent roles in influencing Aβ42 and Aβ40 oligomerization as well as Aβ42 toxicity [3][4][5]. Aβ oligomeric assemblies frequently coalesce into protofibrils, and can subsequently mature into fibrils that form amyloid plaques [6]. The importance of soluble Aβ oligomers in the etiology of AD is well established, while the precise role of Aβ fibrils in AD pathogenesis remains unclear [7][8][9]. ...
Background
The accumulation of amyloid beta (Aβ) peptides in fibrils is prerequisite for Alzheimer’s disease (AD). Our understanding of the proteins that promote Aβ fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts.
Methods
To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy. We benchmarked the success of our purifications using electron microscopy, amyloid dyes, and a large panel of Aβ immunoassays. Tandem mass-spectrometry based proteomic analysis workflows provided quantitative measures of the amyloid fibril proteome. These methods allowed us to compare amyloid fibril composition from human AD brains, three amyloid mouse models, transgenic Aβ42 flies, and Aβ42 seeded cultured neurons.
Results
Amyloid fibrils are primarily composed by Aβ42 and unexpectedly harbor Aβ38 but generally lack Aβ40 peptides. Multidimensional quantitative proteomics allowed us to redefine the fibril proteome by identifying 20 new amyloid-associated proteins. Notably, we confirmed 57 previously reported plaque-associated proteins. We validated a panel of these proteins as bona fide amyloid-interacting proteins using antibodies and orthogonal proteomic analysis. One metal-binding chaperone metallothionein-3 is tightly associated with amyloid fibrils and modulates fibril formation in vitro . Lastly, we used a transgenic Aβ42 fly model to test if knock down or over-expression of fibril-interacting gene homologues modifies neurotoxicity. Here, we could functionally validate 20 genes as modifiers of Aβ42 toxicity in vivo.
Conclusions
These discoveries and subsequent confirmation indicate that fibril-associated proteins play a key role in amyloid formation and AD pathology.
... The role of Aβ38 remains unknown, but according to some studies it is less prone to aggregation and less toxic than Aβ42 and could have protective properties, interfering with the conversion of Aβ40 and Aβ42 to a β-sheet-rich aggregate, potentially in a sex-dependent manner. (Bursavich et al., 2016;Mekala et al., 2020;Quartey et al., 2021). Recently it was also reported that Aβ38 (alone, but not in combination with Aβ42) can reverse the negative impact of Aβ42 on LTP and mitochondrial function in acute hippocampal slices and APOE-ε4 + human fibroblast cultures (Quartey et al., 2021). ...
... (Bursavich et al., 2016;Mekala et al., 2020;Quartey et al., 2021). Recently it was also reported that Aβ38 (alone, but not in combination with Aβ42) can reverse the negative impact of Aβ42 on LTP and mitochondrial function in acute hippocampal slices and APOE-ε4 + human fibroblast cultures (Quartey et al., 2021). ...
Background
Largely recognized too late, Alzheimer’s disease (AD) affects around 46 million people worldwide. The etiology of AD is still puzzling the scientific community, and its drug development and clinical trials have had high failure rate. In the recent decade, numerous studies targeting amyloid‐β peptides (Aβ) and their metabolism have been tested in patients, raising additional questions regarding AD.
Method
In order to integrate recent (from 2014) findings and analyze their clinical potential, we conducted a systematic review of investigational studies, follow‐up studies and review articles, that focus on anti‐Aβ therapies. The records were required to investigate the safety, tolerability, pharmacokinetics, efficacy, or immunogenicity of anti‐amyloid treatments in human population, excluding short and interrupted studies (<10 days), and clinical trials concerning other pathologies or comorbidities.
Result
Thus far, experimental therapies directed against Aβ have not been able to significantly reduce the progress of AD and memory impairment. The majority of therapeutic strategies were focused on amyloid precursor protein processing, and active or passive immunotherapy. Fewer studies evaluated drugs affecting Aβ misfolding, aggregation or clearance. Targeting β‐ and γ‐secretase have had unwanted results, but the activators of α‐secretase and immunotherapy against Aβ oligomers are giving some promise. Recent FDA approval and EU refusal of aducanumab sparked hopes and controversies, since the latest trial data confirmed amyloid plaque removal, without clear cognitive benefits.
Conclusion
Targeting only Aβ was not able to significantly improve the cognition of patients or modify the AD progression. The research is slowly moving toward multifunctional drugs targeting factors that precede the Aβ aggregation process, i.e., pathologic positive feedback loop linking Aβ production and other factors, such as neuronal hyperexcitability, neuroinflammation, or oxidative stress. Further development of early detection biomarkers, antibodies and additional agents that would act on both amyloid and non‐amyloid targets, could be the key to slowing down this global epidemic.
Funding
This work was supported by grants BFU2017‐82494‐P and PID2020‐115823GB‐I00 funded by MCIN/AEI/ 10.13039/501100011033 and by ERDF “A way of making Europe” by the European Union; both to LJ‐D and JDN‐L. DJ held a predoctoral scholarship from Plan Propio de Investigación–ESF Programme of University of Castilla‐La Mancha.
... However, Aβ peptides are generated when APP undergoes sequential cleavage by β-and γ-secretases [8,9] . Aβ is a polypeptide with various amounts (e.g., 37-43 [10] ) of amino acid residues in length [10][11][12][13] . At the C-termini, longer Aβ variants incorporate additional residues from the APP transmembrane domain. ...
... However, Aβ peptides are generated when APP undergoes sequential cleavage by β-and γ-secretases [8,9] . Aβ is a polypeptide with various amounts (e.g., 37-43 [10] ) of amino acid residues in length [10][11][12][13] . At the C-termini, longer Aβ variants incorporate additional residues from the APP transmembrane domain. ...
... Longer variants (e.g., Aβ42) impair hippocampal long-term potentiation (LTP) whereas the shorter Aβ peptides (e.g., Aβ37, Aβ38, Aβ39, and Aβ40) are less likely to evoke any overt effect on synaptic function [23][24][25] . Aβ38 is found to be able to rescue Aβ40-mediated mitochondrial dysfunction and Aβ42-mediated LTP impairment, although Aβ38 shows a modest inhibition of LTP [10] . Additionally, when compared with Aβ42/40 in CSF, the Aβ 37/42 ratio can more sensitively detect γ-secretase dysfunction and distinguish cognitively normal subjects from Alzheimer's disease patients [26] . ...
Alzheimer's disease imposes a severe burden. Alzheimer's pathology can be assessed and defined by Aβ and tau biomarkers. Pathogenesis of Alzheimer's disease is a continuum that ranges from a cognitively unimpaired stage to severely-demented status. For all three variants of Alzheimer's disease, i.e., autosomal dominant Alzheimer's disease, APOE ε4-related sporadic Alzheimer's disease and APOE ε4-unrelated sporadic Alzheimer's disease, the preclinical period of Alzheimer's disease may be a long period lasting several decades. Developing an effective disease-modifying therapy for Alzheimer's disease is still a challenge. However, healthy lifestyles, education, social support, and health care have been proven to play critical roles in maintaining brain health in older adults and reducing the incidence and prevalence of Alzheimer's disease. To prevent/postpone the progression of Alzheimer's disease, potential risk factors should be identified and modified as early as possible. The ultra-early screening of Alzheimer's disease focuses on detecting at-risk people manifesting "Transitional cognitive decline", a stage earlier than mild cognitive impairment (MCI) because it is a better time window for intervention than MCI. However, many studies show that people in this stage exhibit hyperactivation in some brain regions (e.g., hippocampus) and slightly better cognitive performance when compared with healthy controls. Such coexistence of hyperactivation and better cognitive performance is probably a result of toxicological stimuli induced by glutamate and fatty acids rather than compensation. Due to the existence of the toxic irritation-induced, increased cognitive performance, the very early stage of Alzheimer's disease may be more appropriately referred to as a stage of "Transitional cognitive dysfunction" instead of "Transitional cognitive decline".
... Mostly the biomarker scrutiny focuses primarily on Aβ42 and Aβ40. However, other Aβ variant like Aβ43 has also been highlighted to be generated in AD patients and has a tendency to aggregate as plaques, while Aβ37 and Aβ38 are formed in cognitively intact individuals and especially target the vasculature (Wiltfang et al. 2002;Quartey et al. 2021). The levels of Aβ38 have been observed to be elevated in earlyonset/familial AD patients and AD-associated amyloidosis experiments (Czirr et al. 2008;Reinert et al. 2014). ...
The development of early non-invasive diagnosis methods and identification of novel biomarkers are necessary for managing Alzheimer’s disease (AD) and facilitating effective prognosis and treatment. AD has multi-factorial nature and involves complex molecular mechanism, which causes neuronal degeneration. The primary challenges in early AD detection include patient heterogeneity and lack of precise diagnosis at the preclinical stage. Several cerebrospinal fluid (CSF) and blood biomarkers have been proposed to show excellent diagnosis ability by identifying tau pathology and cerebral amyloid beta (Aβ) for AD. Intense research endeavors are being made to develop ultrasensitive detection techniques and find potent biomarkers for early AD diagnosis. To mitigate AD worldwide, understanding various CSF biomarkers, blood biomarkers, and techniques that can be used for early diagnosis is imperative. This review attempts to provide information regarding AD pathophysiology, genetic and non-genetic factors associated with AD, several potential blood and CSF biomarkers, like neurofilament light, neurogranin, Aβ, and tau, along with biomarkers under development for AD detection. Besides, numerous techniques, such as neuroimaging, spectroscopic techniques, biosensors, and neuroproteomics, which are being explored to aid early AD detection, have been discussed. The insights thus gained would help in finding potential biomarkers and suitable techniques for the accurate diagnosis of early AD before cognitive dysfunction.
Graphical Abstract
... Emerging data suggest that even small amounts of Aβ37 and Aβ38 reduce the ability of Aβ42 to aggregate (15). Aβ37 and Aβ38 can ameliorate the phenotypes of degeneration models, possibly by reducing the amyloidogenic potential of longer Aβs (15,38,39). Higher cerebrospinal fluid Aβ38 has recently even been shown to be associated with reduced cognitive decline in AD patients (16). ...
Imbalances in the amounts of amyloid-β peptides (Aβ) generated by the membrane proteases β- and γ-secretase are considered as a trigger of Alzheimer´s disease (AD). Cell-free studies of γ-secretase have shown that increasing membrane thickness modulates Aβ generation, but it has remained unclear if these effects are translatable to cells. Here we show that the very long chain fatty acid erucic acid (EA) triggers acyl chain remodeling in AD cell models, resulting in substantial lipidome alterations which included increased esterification of EA in membrane lipids. Membrane remodeling enhanced γ-secretase processivity, resulting in the increased production of the potentially beneficial Aβ37 and/or Aβ38 species in multiple cell lines. Unexpectedly, we found that the membrane remodeling stimulated total Aβ secretion by cells expressing WT γ-secretase, but lowered it for cells expressing an aggressive familial AD mutant γ-secretase. We conclude that EA-mediated modulation of membrane composition is accompanied by complex lipid homeostatic changes that can impact amyloidogenic processing in different ways and elicit distinct γ-secretase responses, providing critical implications for lipid-based AD treatment strategies.
