Journal of Alzheimer's Disease - Volume 96, issue 2

Authors: Ben Khedher, Mohamed Raâfet | Haddad, Mohamed | Fulop, Tamas | Laurin, Danielle | Ramassamy, Charles

Article Type: Research Article

Abstract: Background: The perplex interrelation between circulating extracellular vesicles (cEVs) and amyloid-β (Aβ) deposits in the context of Alzheimer’s disease (AD) is poorly understood. Objective: This study aims to 1) analyze the possible cross-linkage of the neurotoxic amyloid-β oligomers (oAβ) to the human cEVs, 2) identify cEVs corona proteins associated with oAβ binding, and 3) analyze the distribution and expression of targeted cEVs proteins in preclinical participants converted to AD 5 years later (Pre-AD). Methods: cEVs were isolated from 15 Pre-AD participants and 15 healthy controls selected from the Canadian Study of Health and Aging. Biochemical, clinical, …lipid, and inflammatory profiles were measured. oAβ and cEVs interaction was determined by nanoparticle tracking analysis and proteinase K digestion. cEVs bound proteins were determined by ELISA. Results: oAβ were trapped by cEVs and were topologically bound to their external surface. We identified surface-exposed proteins functionally able to conjugate oAβ including apolipoprotein J (apoJ), apoE and RAGE, with apoJ being 30- to 130-fold higher than RAGE and apoE, respectively. The expression of cEVs apoJ was significantly lower in Pre-AD up to 5 years before AD onset. Conclusion: Our findings suggest that cEVs might participate in oAβ clearance and that early dysregulation of cEVs could increase the risk of conversion to AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, apolipoprotein J, extracellular vesicles

DOI: 10.3233/JAD-230823

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 813-825, 2023

Authors: Alrouji, Mohammed | Majrashi, Taghreed A. | Alhumaydhi, Fahad A. | Zari, Ali | Zari, Talal A. | Al Abdulmonem, Waleed | Sharaf, Sharaf E. | Shahwan, Moyad | Anwar, Saleha | Shamsi, Anas | Atiya, Akhtar

Article Type: Research Article

Abstract: Background: Tyrosine-protein kinase Fyn (Fyn) is a critical signaling molecule involved in various cellular processes, including neuronal development, synaptic plasticity, and disease pathogenesis. Dysregulation of Fyn kinase has been implicated in various complex diseases, including neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases, as well as different cancer types. Therefore, identifying small molecule inhibitors that can inhibit Fyn activity holds substantial significance in drug discovery. Objective: The aim of this study was to identify potential small-molecule inhibitors among bioactive phytoconstituents against tyrosine-protein kinase Fyn. Methods: Through a comprehensive approach involving molecular docking, drug likeliness filters, and …molecular dynamics (MD) simulations, we performed a virtual screening of a natural compounds library. This methodology aimed to pinpoint compounds potentially interacting with Fyn kinase and inhibiting its activity. Results: This study finds two potential natural compounds: Dehydromillettone and Tanshinone B. These compoundsdemonstrated substantial affinity and specific interactions towards the Fyn binding pocket. Their conformations exhibitedcompatibility and stability, indicating the formation of robust protein-ligand complexes. A significant array of non-covalentinteractions supported the structural integrity of these complexes. Conclusion: Dehydromillettone and Tanshinone B emerge as promising candidates, poised for further optimization as Fynkinase inhibitors with therapeutic applications. In a broader context, this study demonstrates the potential of computationaldrug discovery, underscoring its utility in identifying compounds with clinical significance. The identified inhibitors holdpromise in addressing a spectrum of cancer and neurodegenerative disorders. However, their efficacy and safety necessitatevalidation through subsequent experimental studies. Show more

Keywords: Alzheimer’s disease, drug discovery, molecular dynamics simulations, phytochemicals, tyrosine-protein kinase Fyn, virtual screening

DOI: 10.3233/JAD-230828

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 827-844, 2023

Authors: Dong, Yi | Hou, Tingting | Li, Yuanjing | Liu, Rui | Cong, Lin | Liu, Keke | Liu, Cuicui | Han, Xiaolei | Ren, Yifei | Tang, Shi | Winblad, Bengt | Blennow, Kaj | Wang, Yongxiang | Du, Yifeng | Qiu, Chengxuan

Article Type: Research Article

Abstract: Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. …Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42 /Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum. Show more

Keywords: Alzheimer’s disease, diagnostic accuracy, mild cognitive impairment, plasma biomarkers, population-based study

DOI: 10.3233/JAD-230932

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 845-858, 2023

Article Type: Correction

DOI: 10.3233/JAD-239011

Citation: Journal of Alzheimer's Disease, vol. 96, no. 2, pp. 859-860, 2023