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

Authors: Leyton, Esteban | Matus, Diego | Espinoza, Sandra | Benitez, José Matías | Cortés, Bastián I. | Gomez, Wileidy | Arévalo, Nohela B. | Murgas, Paola | Manque, Patricio | Woehlbier, Ute | Duran-Aniotz, Claudia | Hetz, Claudio | Behrens, María Isabel | SanMartín, Carol D. | Nassif, Melissa

Article Type: Research Article

Abstract: Background: Disturbances in the autophagy/endolysosomal systems are proposed as early signatures of Alzheimer’s disease (AD). However, few studies are available concerning autophagy gene expression in AD patients. Objective: To explore the differential expression of classical genes involved in the autophagy pathway, among them a less characterized one, DEF8 (Differentially expressed in FDCP 8), initially considered a Rubicon family member, in peripheral blood mononuclear cells (PBMCs) from individuals with mild cognitive impairment (MCI) and probable AD (pAD) and correlate the results with the expression of DEF8 in the brain of 5xFAD mice. Method: By real-time PCR …and flow cytometry, we evaluated autophagy genes levels in PBMCs from MCI and pAD patients. We evaluated DEF8 levels and its localization in brain samples of the 5xFAD mice by real-time PCR, western blot, and immunofluorescence. Results: Transcriptional levels of DEF8 were significantly reduced in PBMCs of MCI and pAD patients compared with healthy donors, correlating with the MoCA and MoCA-MIS cognitive tests scores. DEF8 protein levels were increased in lymphocytes from MCI but not pAD, compared to controls. In the case of brain samples from 5xFAD mice, we observed a reduced mRNA expression and augmented protein levels in 5xFAD compared to age-matched wild-type mice. DEF8 presented a neuronal localization. Conclusion: DEF8, a protein proposed to act at the final step of the autophagy/endolysosomal pathway, is differentially expressed in PBMCs of MCI and pAD and neurons of 5xFAD mice. These results suggest a potential role for DEF8 in the pathophysiology of AD. Show more

Keywords: Alzheimer’s disease, autophagy, DEF8, lymphocytes, lysosome, mild cognitive impairment, Rubicon

DOI: 10.3233/JAD-201264

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S163-S178, 2021

Authors: Chaparro, Diego | Flores-Gaspar, Areli | Alí-Torres, Jorge

Article Type: Research Article

Abstract: Background: Redox active metal cations, such as Cu2 + , have been related to induce amyloid plaques formation and oxidative stress, which are two of the key events in the development of Alzheimer’s disease (AD) and others metal promoted neurodegenerative diseases. In these oxidative events, standard reduction potential (SRP) is an important property especially relevant in the reactive oxygen species formation. Objective: The SRP is not usually considered for the selection of drug candidates in anti-AD treatments. In this work, we present a computational protocol for the selection of multifunctional ligands with suitable metal chelating, pharmacokinetics, and redox properties. …Methods: The filtering process is based on quantum chemical calculations and the use of in silico tools. Calculations of SRP were performed by using the M06-2X density functional and the isodesmic approach. Then, a virtual screening technique (VS) was used for similar structure search. Results: Protocol application allowed the assessment of chelating, drug likeness, and redox properties of copper ligands. Those molecules showing the best features were selected as molecular scaffolds for a VS procedure in order to obtain related compounds. After applying this process, we present a list of candidates with suitable properties to prevent the redox reactions mediated by copper(II) ion. Conclusion: The protocol incorporates SRP in the filtering stage and can be effectively used to obtain a set of potential drug candidates for AD treatments. Show more

Keywords: Alzheimer’s disease, antioxidants, computer-aided drug design, density functional theory (DFT) calculations, drug discovery, metal complexes, redox

DOI: 10.3233/JAD-200911

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S179-S193, 2021

Authors: Cuervo-Zanatta, Daniel | Garcia-Mena, Jaime | Perez-Cruz, Claudia

Article Type: Research Article

Abstract: Background: Normal aging is accompanied by cognitive deficiencies, affecting women and men equally. Aging is the main risk factor for Alzheimer’s disease (AD), with women having a higher risk. The higher prevalence of AD in women is associated with the abrupt hormonal decline seen after menopause. However, other factors may be involved in this sex-related cognitive decline. Alterations in gut microbiota (GM) and its bioproducts have been reported in AD subjects and transgenic (Tg) mice, having a direct impact on brain amyloid-β pathology in male (M), but not in female (F) mice. Objective: The aim of this work …was to determine GM composition and cognitive dysfunction in M and F wildtype (WT) and Tg mice, in a sex/genotype segregation design. Methods: Anxiety, short term working-memory, spatial learning, and long-term spatial memory were evaluated in 6-month-old WT and Tg male mice. Fecal short chain fatty acids were determined by chromatography, and DNA sequencing and bioinformatic analyses were used to determine GM differences. Results: We observed sex-dependent differences in cognitive skills in WT mice, favoring F mice. However, the cognitive advantage of females was lost in Tg mice. GM composition showed few sex-related differences in WT mice. Contrary, Tg-M mice presented a more severe dysbiosis than Tg-F mice. A decreased abundance of Ruminococcaceae was associated with cognitive deficits in Tg-F mice, while butyrate levels were positively associated with better working- and object recognition-memory in WT-F mice. Conclusion: This report describes a sex-dependent association between GM alterations and cognitive impairment in a mice model of AD. Show more

Keywords: Anxiety, APP/PS1 mice, dysbiosis, high-throughput DNA sequencing, short-chain fatty acids, spatial memory, wildtype littermates

DOI: 10.3233/JAD-201367

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S195-S214, 2021

Authors: Santiago-Castañeda, Cindy | Segovia-Oropeza, Marysol | Concha, Luis | Orozco-Suárez, Sandra Adela | Rocha, Luisa

Article Type: Research Article

Abstract: Background: Severe traumatic brain injury (TBI), an important risk factor for Alzheimer’s disease, induces long-term hippocampal damage and hyperexcitability. On the other hand, studies support that propylparaben (PPB) induces hippocampal neuroprotection in neurodegenerative diseases. Objective: Experiments were designed to evaluate the effects of subchronic treatment with PPB on TBI-induced changes in the hippocampus of rats. Methods: Severe TBI was induced using the lateral fluid percussion model. Subsequently, rats received subchronic administration with PPB (178 mg/kg, TBI+PPB) or vehicle (TBI+PEG) daily for 5 days. The following changes were examined during the experimental procedure: sensorimotor dysfunction, changes in hippocampal …excitability, as well as neuronal damage and volume. Results: TBI+PEG group showed sensorimotor dysfunction (p  < 0.001), hyperexcitability (64.2%, p  < 0.001), and low neuronal preservation ipsi- and contralateral to the trauma. Magnetic resonance imaging (MRI) analysis revealed lower volume (17.2%; p  < 0.01) and great damage to the ipsilateral hippocampus. TBI+PPB group showed sensorimotor dysfunction that was partially reversed 30 days after trauma. This group showed hippocampal excitability and neuronal preservation similar to the control group. However, MRI analysis revealed lower hippocampal volume (p  < 0.05) when compared with the control group. Conclusion: The present study confirms that post-TBI subchronic administration with PPB reduces the long-term consequences of trauma in the hippocampus. Implications of PPB as a neuroprotective strategy to prevent the development of Alzheimer’s disease as consequence of TBI are discussed. Show more

Keywords: Alzheimer’s disease, brain trauma, hippocampus, neuroprotection, propylparaben

DOI: 10.3233/JAD-200914

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S215-S226, 2021

Authors: Flores-Cuadra, Julio A. | Madrid, Alanna | Fernández, Patricia L. | Pérez-Lao, Ambar R. | Oviedo, Diana C. | Britton, Gabrielle B. | Carreira, Maria B.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-β plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-β transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary …alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches. Show more

Keywords: Dementia, disease models, drug discovery, rodents

DOI: 10.3233/JAD-200870

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S227-S250, 2021

Authors: Gil, Mario | Alliey-Rodriguez, Ney | Lopez-Alvarenga, Juan Carlos | Diego, Vincent | Gaona, Ciro A. | Mata, Ledys | Pirela, Rosa V. | Chavez, Carlos A. | de Erausquin, Gabriel A. | Melgarejo, Jesus D. | Maestre, Gladys E.

Article Type: Research Article

Abstract: Background: Neuropsychiatric symptoms play an important role in diagnosing and clinical follow-up of cognitive impairment and dementia. Objective: We investigated the relationship between neuropsychiatric symptoms, cognitive impairment, and dementia in Hispanics. Methods: We included 529 participants (age ≥40 years) from the Maracaibo Aging Study with standardized neuropsychiatric assessments, including the Neuropsychiatric Inventory (NPI). Based on the Clinical Dementia Rating and the Mini-Mental State Examination scores, participants’ cognitive status was categorized into normal cognition, mild/moderate, and severe cognitive impairment. Diagnosis of dementia was established in a consensus conference. Statistical analyses included multivariable logistic regression models and …area under the curve (AUC). Results: The mean age of participants was 59.3 years, and 71.8%were women. The proportion of dementia was 6.8%. Disturbed sleep, anxiety, and depression were the most common neuropsychiatric symptoms in the study sample. In crude analyses, the proportions of hallucinations, aberrant motor behavior, agitation/aggression, apathy, delusions, irritability, eating disturbance, depression, and euphoria were differently distributed among cognitive status groups (p  < 0.05). After accounting for confounders, aberrant motor behavior and agitation/aggression remained significantly associated with cognitive impairment and dementia (p  < 0.05). The inclusion of the NPI domains significantly improved the AUC to discriminate severe cognitive impairment and dementia compared to a basic model that included sex, age, education, alcohol, obesity, serum glucose, total cholesterol, hypertension, and stroke. Conclusion: Neuropsychiatric symptoms are associated with severe cognitive impairment and dementia. The addition of NPI items to the global cognitive assessment might help early detection of dementia in primary care settings. Show more

Keywords: Aging, Alzheimer’s disease, cognitive impairment, dementia, Hispanics, neuropsychiatric inventory

DOI: 10.3233/JAD-201144

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S251-S261, 2021

Authors: Castro, Fernando | Melgarejo, Jesús | Chavez, Carlos A. | de Erausquin, Gabriel A. | Terwilliger, Joseph D. | Lee, Joseph H. | Maestre, Gladys E.

Article Type: Research Article

Abstract: Background: Very few studies have investigated the association between total plasma homocysteine (tHcy) and depressive symptoms in older Hispanics. Objective: To test the hypothesis that high tHcy associates with depressive symptoms in older Hispanics. Methods: A total of 1,418 participants .55 years old from the Maracaibo Aging Study (MAS) underwent standardized neurological, neuropsychiatric, and cardiovascular assessments. The Neuropsychiatric Inventory Depression Subscale (NPId) was used to assess the burden of depressive symptoms. The tHcy levels and other biochemical parameters in blood samples were measured. Univariate and multivariate logistic regression models were applied. Results: Participants with …depressive symptoms had higher levels of tHcy than those without (15.1 versus 13.9 µmol/L; p = 0.009). Elevated tHcy levels were associated with depressive symptoms after adjusting for age, sex, education, smoking, diabetes, hypertension, alcohol intake, stroke, and dementia (OR = 1.58; 95% CI, 1.18–2.12). Conclusion: Elevated levels of tHcy were associated with depressive symptoms in older Hispanics living under the nutritional and environmental conditions of a developing country. Show more

Keywords: Aging, cohort studies, depressive symptoms, elderly, Hispanics, homocysteine, Latinos

DOI: 10.3233/JAD-201062

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S263-S269, 2021

Authors: Castillo-Mendieta, Tzayaka | Arana-Lechuga, Yoaly | Campos-Peña, Victoria | Sosa, Ana Luisa | Orozco-Suarez, Sandra | Pinto-Almazán, Rodolfo | Segura-Uribe, Julia | Javier Rodríguez-Sánchez de Tagle, Aldo | Ruiz-Sánchez, Elizabeth | Guerra-Araiza, Christian

Article Type: Research Article

Abstract: Background: Alzheimer’s disease (AD) causes memory deficit and alterations in other cognitive functions, mainly in adults over 60 years of age. As the diagnosis confirmation is performed by a postmortem neuropathological examination of the brain, this disease can be confused with other types of dementia at early stages. About 860,000 Mexicans are affected by dementia, most of them with insufficient access to adequate comprehensive health care services. Plasma biomarkers could be a rapid option for early diagnosis of the disease. Objective: This study aimed to analyze some plasma biomarkers (amyloid-β, tau, and lipids) in Mexican AD patients and …control subjects with no associated neurodegenerative diseases. Methods: Plasma amyloid-β peptides (Aβ40 and Aβ42 ), total and phosphorylated tau protein (T-tau and P-tau), and cholesterol and triglyceride levels were quantified by enzyme-linked immunosorbent assay in AD patients and control subjects. Results: In Mexican AD patients, we found significantly lower levels of Aβ42 (p  < 0.05) compared to the control group. In contrast, significantly higher levels of P-tau (p  < 0.05) and triglycerides (p  < 0.05) were observed in AD patients compared to controls. Furthermore, a significant correlation was found between the severity of dementia and plasma P-tau levels, Aβ42 /Aβ40 and P-tau/T-tau ratios, and triglycerides concentrations. This correlation increased gradually with cognitive decline. Conclusion: The detection of these plasma biomarkers is an initial step in searching for a timely, less invasive, and cost-efficient diagnosis in Mexicans. Show more

Keywords: Alzheimer’s disease, amyloid-β, early diagnosis, Mexican patients, tau protein

DOI: 10.3233/JAD-200912

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S271-S281, 2021

Authors: Arévalo, Nohela B. | Castillo-Godoy, Daniela P. | Espinoza-Fuenzalida, Italo | Rogers, Nicole K. | Farias, Gonzalo | Delgado, Carolina | Henriquez, Mauricio | Herrera, Luisa | Behrens, María Isabel | SanMartín, Carol D.

Article Type: Research Article

Abstract: Background: Amyloid-β peptide (Aβ) deposition in Alzheimer’s disease (AD) is due to an imbalance in its production/clearance rate. Aβ is transported across the blood-brain barrier by LRP1 and P-gp as efflux transporters and RAGE as influx transporter. Vitamin D deficit and polymorphisms of the vitamin D receptor (VDR ) gene are associated with high prevalence of mild cognitive impairment (MCI) and AD. Further, vitamin D promotes the expression of LRP1 and P-gp in AD-animal model brains. Objective: To associate VDR polymorphisms Apa I (rs7975232), Taq I (rs731236), and Fok I (rs2228570) with the risk of developing MCI …in a Chilean population, and to evaluate the relationship of these polymorphisms to the expression of VDR and Aβ-transporters in peripheral blood mononuclear cells (PBMCs). Methods: VDR polymorphisms Apa I, Taq I, and Fok I were determined in 128 healthy controls (HC) and 66 MCI patients. mRNA levels of VDR and Aβ-transporters were evaluated in subgroups by qPCR. Results: Alleles A of Apa I and C of Taq I were associated with a lower risk of MCI. HC with the Apa I AA genotype had higher mRNA levels of P-gp and LRP1 , while the expression of VDR and RAGE were higher in MCI patients and HC. For Fok I, the TC genotype was associated with lower expression levels of Aβ-transporters in both groups. Conclusion: We propose that the response to vitamin D treatment will depend on VDR polymorphisms, being more efficient in carriers of protective alleles of Apa I polymorphism. Show more

Keywords: Alzheimer’s disease, ATP binding cassette transporter, cognitive dysfunction, receptor for advanced glycation end products (RAGE), single nucleotide polymorphism, vitamin D, vitamin D receptor

DOI: 10.3233/JAD-201031

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S283-S297, 2021

Authors: Ayala-Grosso, Carlos | Torrico, Fátima | Ledezma-Ruiz, Margot | Busolo-Pons, Maria

Article Type: Research Article

Abstract: Background: Understanding diurnal secretion of cortisol in association with behavioral attitudes as a result of perception of unsafety environment is a main interest in prospective studies establishing the impact of chronic stress in cognitive processes. Adaptive secretion of cortisol, a biomarker of the hypothalamic-hypophysis-adrenal (HPA) axis, has been correlated with perception of uncertainty in surroundings as a consequence of perseverative cognition and unconscious thoughts. Objective: To determine whether diurnal secretion pattern of cortisol was associated with behavioral attitudes indexes generated from answers to standardized questionnaires from Panamerican Health Organization/World Health Organization (PAHO/WHO) agencies. Methods: Saliva cortisol …dynamic range was evaluated by immuno-essay. Cortisol awakening response (CAR) and total secreted cortisol was established in a cross-sectional study of four saliva samples per day from volunteers (n  = 135) between 19 and 65 years old. Results: Saliva cortisol dynamic range followed a significant decay along the day. Reduction of social interaction and increase of defensive behavioral attitude was associated with older groups of age. In this study, two subgroups of subjects with a steeper cortisol secretion (slope significant non-zero), and flatter cortisol secretion (slope no significant non-zero) were detected. Noticeable, we determined an association between measurements of cortisol secretion from subjects with a flatter cortisol dynamic range and behavioral defensive and inhibition of social interaction indexes. Conclusion: These findings suggested chronical dysregulation of HPA axis as a result of perseverative cognitive perception of unsafety environment which may be precedent to cognitive impairment in the population. Show more

Keywords: Alzheimer’s disease, behavioral attitude, chronic stress, cognition, cortisol, mild cognitive impairment, perception, ruminant thoughts

DOI: 10.3233/JAD-200886

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S299-S312, 2021

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