Journal of Alzheimer's Disease - Volume 82, issue s1

Authors: Oviedo, Diana C. | Perez-Lao, Ambar R. | Flores-Cuadra, Julio A. | Villarreal, Alcibiades E. | Carreira, Maria B. | Grajales, Shantal A. | Britton, Gabrielle B.

Article Type: Short Communication

Abstract: Apolipoprotein ɛ 4 allele (APOE ɛ 4) is the strongest genetic risk factor for sporadic Alzheimer’s disease (AD), but inconsistencies have arisen in studies with Hispanics. The objective of this study was to explore APOE ɛ 4 expression and cognitive function in a sample of Panamanian older adults, including healthy controls, mild cognitive impairment, and AD. Participants with at least one copy of APOE ɛ 4 had a significantly lower performance in global cognition, verbal memory, executive functions, visuospatial abilities, regardless of diagnosis. The present study contributes to the understanding of the association of APOE ɛ …4 and impairment in specific cognitive domains in elderly Hispanics. Show more

Keywords: Alzheimer’s disease, biomarkers, cognition, memory deficits

DOI: 10.3233/JAD-200921

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S313-S319, 2021

Authors: Orjuela, Adrian | Lakey-Beitia, Johant | Mojica-Flores, Randy | Hegde, Muralidhar L. | Lans, Isaias | Alí-Torres, Jorge | Rao, K.S.

Article Type: Research Article

Abstract: Background: The most important hallmark in the neuropathology of Alzheimer’s disease (AD) is the formation of amyloid-β (Aβ) fibrils due to the misfolding/aggregation of the Aβ peptide. Preventing or reverting the aggregation process has been an active area of research. Naturally occurring products are a potential source of molecules that may be able to inhibit Aβ42 peptide aggregation. Recently, we and others reported the anti-aggregating properties of curcumin and some of its derivatives in vitro, presenting an important therapeutic avenue by enhancing these properties. Objective: To computationally assess the interaction between Aβ peptide and a set …of curcumin derivatives previously explored in experimental assays. Methods: The interactions of ten ligands with Aβ monomers were studied by combining molecular dynamics and molecular docking simulations. We present the in silico evaluation of the interaction between these derivatives and the Aβ42 peptide, both in the monomeric and fibril forms. Results: The results show that a single substitution in curcumin could significantly enhance the interaction between the derivatives and the Aβ42 monomers when compared to a double substitution. In addition, the molecular docking simulations showed that the interaction between the curcumin derivatives and the Aβ42 monomers occur in a region critical for peptide aggregation. Conclusion: Results showed that a single substitution in curcumin improved the interaction of the ligands with the Aβ monomer more so than a double substitution. Our molecular docking studies thus provide important insights for further developing/validating novel curcumin-derived molecules with high therapeutic potential for AD. Show more

Keywords: Alzheimer’s disease, Aβ monomer, Aβ42 fibril, AutoDock Vina, AutoDock 4, curcumin, curcumin derivatives, molecular docking, Smina

DOI: 10.3233/JAD-200941

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S321-S333, 2021

Authors: Lakey-Beitia, Johant | Burillo, Andrea M. | La Penna, Giovanni | Hegde, Muralidhar L. | Rao, K.S.

Article Type: Review Article

Abstract:  Alzheimer’s disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide. The pathology of this multifactorial disease is primarily characterized by the formation of amyloid-β (Aβ) aggregates; however, other etiological factors including metal dyshomeostasis, specifically copper (Cu), zinc (Zn), and iron (Fe), play critical role in disease progression. Because these transition metal ions are important for cellular function, their imbalance can cause oxidative stress that leads to cellular death and eventual cognitive decay. Importantly, these transition metal ions can interact with the amyloid-β protein precursor (AβPP) and Aβ42 peptide, affecting Aβ aggregation and increasing …its neurotoxicity. Considering how metal dyshomeostasis may substantially contribute to AD, this review discusses polyphenols and the underlying chemical principles that may enable them to act as natural chelators. Furthermore, polyphenols have various therapeutic effects, including antioxidant activity, metal chelation, mitochondrial function, and anti-amyloidogenic activity. These combined therapeutic effects of polyphenols make them strong candidates for a moderate chelation-based therapy for AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, metalloproteins, copper, zinc, iron, polyphenols, metal chelation therapy

DOI: 10.3233/JAD-200185

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S335-S357, 2021

Authors: Soto-Mercado, Viviana | Mendivil-Perez, Miguel | Jimenez-Del-Rio, Marlene | Velez-Pardo, Carlos

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) is characterized by structural damage, death, and functional disruption of cholinergic neurons (ChNs) as a result of intracellular amyloid-β (Aβ) aggregation, extracellular neuritic plaques, and hyperphosphorylation of protein tau (p-Tau) overtime. Objective: To evaluate the effect of the synthetic cannabinoid CP55940 (CP) on PSEN1 E280A cholinergic-like nerve cells (PSEN1 ChLNs)—a natural model of familial AD. Methods: Wild type (WT) and PSEN1 ChLNs were exposed to CP (1μM) only or in the presence of the CB1 and CB2 receptors (CB1 Rs, CB2 Rs) inverse agonist SR141716 (1μM) and SR144528 (1μM) respectively, …for 24 h. Untreated or treated neurons were assessed for biochemical and functional analysis. Results: CP in the presence of both inverse agonists (hereafter SR) almost completely inhibits the aggregation of intracellular sAβPPβf and p-Tau, increases ΔΨ m , decreases oxidation of DJ-1Cys106 -SH residue, and blocks the activation of c-Jun, p53, PUMA, and caspase-3 independently of CB1 Rs signaling in mutant ChLNs. CP also inhibits the generation of reactive oxygen species partially dependent on CB1 Rs. Although CP reduced extracellular Aβ42 , it was unable to reverse the Ca2+ influx dysregulation as a response to acetylcholine stimuli in mutant ChLNs. Exposure to anti-Aβ antibody 6E10 (1:300) in the absence or presence of SR plus CP completely recovered transient [Ca2+ ]i signal as a response to acetylcholine in mutant ChLNs. Conclusion: Taken together our findings suggest that the combination of cannabinoids, CB1 Rs inverse agonists, and anti-Aβ antibodies might be a promising therapeutic approach for the treatment of familial AD. Show more

Keywords: Apoptosis, cannabinoids, cholinergic neurons, CP55940, E280A mutation, familial Alzheimer disease, neuronal dysfunction, oxidative stress, PSEN1, sAβPPβf, tau

DOI: 10.3233/JAD-201045

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S359-S378, 2021

Authors: Ibanez, Agustin | Parra, Mario A. | Butler, Christopher | for The Latin America and the Caribbean Consortium on Dementia (LAC-CD)

Article Type: Research Article

Abstract: In comparison with other regions, dementia prevalence in Latin America is growing rapidly, along with the consequent clinical, social, and economic burden upon patients and their families. The combination of fragile health care systems, large social inequalities, and isolated clinical and research initiatives makes the coordination of efforts imperative. The Latin America and the Caribbean Consortium on Dementia (LAC-CD) is a regional organization overseeing and promoting clinical and research activities on dementia. Here, we first provide an overview of the consortium, highlighting the antecedents and current mission. Then, we present the consortium’s regional research, including the multi-partner consortium to expand …dementia research in Latin America (ReDLat), which aims to identify the unique genetic, social, and economic factors that drive Alzheimer’s and frontotemporal dementia presentation in LAC relative to the US. We describe an extension of ReDLat which aims to develop affordable markers of disease subtype and severity using high density EEG. We introduce current initiatives promoting regional diagnosis, visibility, and capacity, including the forthcoming launch of the Latin American Brain Health Institute (BrainLat). We discuss LAC-CD-led advances in brain health diplomacy, including an assessment of responses to the impact of COVID-19 on people with dementia and examining the knowledge of public policies among experts in the region. Finally, we present the current knowledge-to-action framework, which paves the way for a future regional action plan. Coordinated actions are crucial to forging strong regional bonds, supporting the implementation of regional dementia plans, improving health systems, and expanding research collaborations across Latin America. Show more

Keywords: Dementia, genetics, implementation science, LAC-CD, Latin America, neurodegeneration, neuroimaging, regional health, social determinants of health, socioeconomic status

DOI: 10.3233/JAD-201384

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S379-S394, 2021