Jagannatha Rao KS, Gabrielle Britton, Luisa Lilia Rocha Arrieta, Norberto Garcia-Cairasco, Alberto Lazarowski, Adrián Palacios, Antoni Camins Espuny, Ricardo B. Maccioni
Translational Research and Drug Discovery for Neurodegeneration: Challenges for Latin America
Joaquín Araya-Arriagada, Felipe Bello, Gaganashree Shivashankar, David Neira, Claudia Durán-Aniotz, Mónica L. Acosta, María José Escobar, Claudio Hetz, Max Chacón, Adrián G. Palacios
Retinal Ganglion Cells Functional Changes in a Mouse Model of Alzheimer’s Disease Are Linked with Neurotransmitter Alterations
Abstract: Background: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. This neurodegenerative syndrome affects cognition, memory, behavior, and the visual system, particularly the retina. Objective: This work aims to determine whether the 5xFAD mouse, a transgenic model of AD, displays changes in the function of retinal ganglion cells (RGCs) and if those alterations are correlated with changes in the expression of glutamate and gamma-aminobutyric acid (GABA) neurotransmitters. Methods: In young (2–3-month-old) and adult (6-7-month-old) 5xFAD and WT mice, we have studied the physiological response, firing rate, and burst of RGCs to various types of visual stimuli using a multielectrode array system. Results: The firing rate and burst response in 5xFAD RGCs showed hyperactivity at the early stage of AD in young mice, whereas hypoactivity was seen at the later stage of AD in adults. The physiological alterations observed in 5xFAD correlate well with an increase in the expression of glutamate in the ganglion cell layer in young and adults. GABA staining increased in the inner nuclear and plexiform layer, which was more pronounced in the adult than the young 5xFAD retina, altering the excitation/inhibition balance, which could explain the observed early hyperactivity and later hypoactivity in RGC physiology. Conclusion: These findings indicate functional changes may be caused by neurochemical alterations of the retina starting at an early stage of the AD disease.
Ignacio Martínez-García, Rebeca Hernández-Soto, Benjamín Villasana-Salazar, Benito Ordaz, Fernando Peña-Ortega
Alterations in Piriform and Bulbar Activity/Excitability/Coupling upon Amyloid-β Administration in vivo Related to Olfactory Dysfunction
Abstract: Background: Deficits in odor detection and discrimination are premature symptoms of Alzheimer’s disease (AD) that correlate with pathological signs in the olfactory bulb (OB) and piriform cortex (PCx). Similar olfactory dysfunction has been characterized in AD transgenic mice that overproduce amyloid-β (Aβ), which can be prevented by reducing Aβ levels by immunological and pharmacological means, suggesting that olfactory dysfunction depends on Aβ accumulation and Aβ-driven alterations in the OB and/or PCx, as well as on their activation. However, this possibility was not directly tested before. Objective: To characterize the effects of Aβ on OB and PCx excitability/coupling and on olfaction. Methods: Aβ oligomerized solution (containing oligomers, monomers, and protofibrils) or its vehicle were intracerebroventricularlly injected two weeks before OB and PCx excitability and synchrony were evaluated through field recordings in vivo and in brain slices. Synaptic transmission from the OB to the PCx was also evaluated in vitro. Olfaction was assessed through the habituation/dishabituation test. Results: Aβ did not affect lateral olfactory tract transmission into the PCx but reduced odor habituation and cross-habituation. This olfactory dysfunction was related to a reduction of PCx and OB network activity power in vivo. Moreover, the coherence between PCx-OB activities was also reduced by Aβ. Finally, Aβ treatment exacerbated the 4-aminopyridine-induced excitation in the PCx in vitro. Conclusion: Our results show that Aβ-induced olfactory dysfunction involves a complex set of pathological changes at different levels of the olfactory pathway including alterations in PCx excitability and its coupling with the OB. These pathological changes might contribute to hyposmia in AD.
Daymara Mercerón-Martínez*, Cristobal Ibaceta-González*, Claudia Salazar, William Almaguer-Melian, Jorge A. Bergado-Rosado, Adrian G. Palacios *These authors contributed equally to this work.
Alzheimer's Disease, Neural Plasticity, and Functional Recovery
Abstract: Alzheimer's disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-β and phosphorylated tau protein, and is accompanied by a progressive loss of learning and memory. A healthy nervous system is endowed with synaptic plasticity, among others neural plasticity mechanisms, allowing structural and physiological adaptations to changes in the environment. This neural plasticity modification sustains learning and memory, and behavioral changes and is severely affected by pathological and aging conditions, leading to cognitive deterioration. This article reviews critical aspects of AD neurodegeneration as well as therapeutic approaches that restore neural plasticity to provide functional recoveries, including environmental enrichment, physical exercise, transcranial stimulation, neurotrophin involvement, and direct electrical stimulation of the amygdala. In addition, we report recent behavioral results in Octodon degus, a promising natural model for the study of AD that naturally reproduces the neuropathological alterations observed in AD patients during normal aging, including neuronal toxicity, deterioration of neural plasticity, and the decline of learning and memory.
Leonardo Guzman-Martinez, Camila Calfío, Gonzalo A. Farias, Cristian Vilches, Raul Prieto, Ricardo B. Maccioni
New Frontiers in the Prevention, Diagnosis, and Treatment of Alzheimer’s Disease
Abstract: One of the major puzzles in medical research and public health systems worldwide is Alzheimer’s disease (AD), reaching nowadays a prevalence near 50 million people. This is a multifactorial brain disorder characterized by progressive cognitive impairment, apathy, and mood and neuropsychiatric disorders. The main risk of AD is aging; a normal biological process associated with a continuum dynamic involving a gradual loss of people's physical capacities, but with a sound experienced view of life. Studies suggest that AD is a break from normal aging with changes in the powerful functional capacities of neurons as well as in the mechanisms of neuronal protection. In this context, an important path has been opened toward AD prevention considering that there are elements of nutrition, daily exercise, avoidance of toxic substances and drugs, an active social life, meditation, and control of stress, to achieve healthy aging. Here, we analyze the involvement of such factors and how to control environmental risk factors for a better quality of life. Prevention as well as innovative screening programs for early detection of the disease using reliable biomarkers are becoming critical to control the disease. In addition, the failure of traditional pharmacological treatments and search for new drugs has stimulated the emergence of nutraceutical compounds in the context of a “multitarget” therapy, as well as mindfulness approaches shown to be effective in the aging, and applied to the control of AD. An integrated approach involving all these preventive factors combined with novel pharmacological approaches should pave the way for the future control of the disease.
Melanie Hüttenrauch, José Sócrates Lopez-Noguerola, Susana Castro-Obregón
Connecting Mind-Body Therapy-Mediated Effects to Pathological Features of Alzheimer’s Disease
Abstract: Alzheimer’s disease (AD) is a complex, multifactorial neurodegenerative disorder that represents a major and increasing global health challenge. In most cases, the first clinical symptoms of AD are preceded by neuropathological changes in the brain that develop years to decades before their onset. Therefore, research in the last years has focused on this preclinical stage of AD trying to discover intervention strategies that might, if implemented effectively, delay or prevent disease progression. Among those strategies, mind-body therapies such as yoga and meditation have gained increasing interest as complementary alternative interventions. Several studies have reported a positive impact of yoga and meditation on brain health in both healthy older adults and dementia patients. However, the underlying neurobiological mechanisms contributing to these effects are currently not known in detail. More specifically, it is not known whether yogic interventions, directly or indirectly, can modulate risk factors or pathological mechanisms involved in the development of dementia. In this article, we first review the literature on the effects of yogic practices on outcomes such as cognitive functioning and neuropsychiatric symptoms in patients with mild cognitive impairment and dementia. Then, we analyze how yogic interventions affect different risk factors as well as aspects of AD pathophysiology based on observations of studies in healthy individuals or subjects with other conditions than dementia. Finally, we integrate this evidence and propose possible mechanisms that might explain the positive effects of yogic interventions in cognitively impaired individuals.
Miren Ettcheto, Oriol Busquets, Amanda Cano, Elena Sánchez-Lopez, Patricia R. Manzine, Triana Espinosa-Jimenez, Ester Verdaguer, Francesc X. Sureda, Jordi Olloquequi, Ruben D. Castro-Torres, Carme Auladell, Jaume Folch, Gemma Casadesús, Antoni Camins
Pharmacological Strategies to Improve Dendritic Spines in Alzheimer’s Disease
Abstract: To deeply understand late onset Alzheimer's disease (LOAD), it may be necessary to change the concept that it is a disease exclusively driven by aging processes. The onset of LOAD could be associated with a previous peripheral stress at the level of the gut (changes in the gut microbiota), obesity (metabolic stress), and infections, among other systemic/environmental stressors. The onset of LOAD, then, may result from the generation of mild peripheral inflammatory processes involving cytokine production associated with peripheral stressors that in a second step enter the brain and spread out the process causing a neuroinflammatory brain disease. This hypothesis could explain the potential efficacy of Sodium Oligomannate (GV-971), a mixture of acidic linear oligosaccharides that have shown to remodel gut microbiota and slow down LOAD. However, regardless of the origin of the disease, the end goal of LOAD-related preventative or disease modifying therapies is to preserve dendritic spines and synaptic plasticity that underlay and support healthy cognition. Here we discuss how systemic/environmental stressors impact pathways associated with the regulation of spine morphogenesis and synaptic maintenance, including insulin receptor and the brain derived neurotrophic factor signaling. Spine structure remodeling is a plausible mechanism to maintain synapses and provide cognitive resilience in LOAD patients. Importantly, we also propose a combination of drugs targeting such stressors that may be able to modify the course of LOAD by acting on preventing dendritic spines and synapsis loss.
Amalia Merelli, Marisa Repetto, Alberto Lazarowski, Jerónimo Auzmendi
Hypoxia, Oxidative Stress, and Inflammation: Three Faces of Neurodegenerative Diseases
Abstract: The cerebral hypoxia-ischemia can induce a wide spectrum of biologic responses that include depolarization, excitotoxicity, oxidative stress, inflammation, and apoptosis, and result in neurodegeneration. Several adaptive and survival endogenous mechanisms can also be activated giving an opportunity for the affected cells to remain alive, waiting for helper signals that avoid apoptosis. These signals appear to help cells, depending on intensity, chronicity, and proximity to the central hypoxic area of the affected tissue. These mechanisms are present not only in a large list of brain pathologies affecting commonly older individuals, but also in other pathologies such as refractory epilepsies, encephalopathies, or brain trauma, where neurodegenerative features such as cognitive and/or motor deficits sequelae can be developed. The hypoxia inducible factor 1α (HIF-1α) is a master transcription factor driving a wide spectrum cellular response. HIF-1α may induce erythropoietin (EPO) receptor overexpression, which provides the therapeutic opportunity to administer pharmacological doses of EPO to rescue and/or repair affected brain tissue. Intranasal administration of EPO combined with other antioxidant and anti-inflammatory compounds could become an effective therapeutic alternative, to avoid and/or slow down neurodegenerative deterioration without producing adverse peripheral effects.
Oriol Busquets, Antoni Parcerisas, Ester Verdaguer, Miren Ettcheto, Antoni Camins, Carlos Beas-Zarate, Rubén Darío Castro-Torres, Carme Auladell
c-Jun N-Terminal Kinases in Alzheimer's Disease: A Possible Target for The Modulation of the Earliest Alterations
Abstract: Given the highly multifactorial origin of Alzheimer's disease (AD) neuropathology, disentangling and orderly knowing mechanisms involved in sporadic onset are arduous. Nevertheless, when the elements involved are dissected into smaller pieces, the task becomes more accessible. This review aimed to describe the link between c-Jun N-terminal Kinases (JNKs), master regulators of many cellular functions, and the early alterations of AD: synaptic loss and dysregulation of neuronal transport. Both processes have a role in the posterior cognitive decline observed in AD. The manuscript focuses on the molecular mechanisms of glutamatergic, GABA, and cholinergic synapses altered by the presence of amyloid-β aggregates and hyperphosphorylated tau, as well as on several consequences of the disruption of cellular processes linked to neuronal transport that is controlled by the JNK-JIP (c-jun NH2-terminal kinase (JNK)–interacting proteins (JIPs) complex, including the transport of AβPP or autophagosomes.
Rafael Andrés Posada-Duque, Gloria Patricia Cardona-Gómez
CDK5 Targeting as a Therapy for Recovering Neurovascular Unit Integrity in Alzheimer’s Disease
Abstract: The neurovascular unit (NVU) is responsible for synchronizing the energetic demand, vasodynamic changes, and neurochemical and electrical function of the brain through a closed and interdependent interaction of cell components conforming to brain tissue. In this review, we will focus on cyclin-dependent kinase 5 (CDK5) as a molecular pivot, which plays a crucial role in the healthy function of neurons, astrocytes, and the endothelium and is implicated in the cross-talk of cellular adhesion signaling, ion transmission, and cytoskeletal remodeling, thus allowing the individual and interconnected homeostasis of cerebral parenchyma. Then, we discuss how CDK5 overactivation affects the integrity of the NVU in Alzheimer’s disease (AD) and cognitive impairment; we emphasize how CDK5 is involved in the excitotoxicity spreading of glutamate and Ca2+ imbalance under acute and chronic injury. Additionally, we present pharmacological and gene therapy strategies for producing partial depletion of CDK5 activity on neurons, astrocytes, or endothelium to recover neuroplasticity and neurotransmission, suggesting that the NVU should be the targeted tissue unit in protective strategies. Finally, we conclude that CDK5 could be effective due to its intervention on astrocytes by its end feet on the endothelium and neurons, acting as an intermediary cell between systemic and central communication in the brain. This review provides integrated guidance regarding the pathogenesis of and potential repair strategies for AD.
Esteban Leyton*, Diego Matus*, Sandra Espinoza, José Matías Benitez, Bastián I. Cortes, Wileidy Gomez, Nohela B. Arévalo, Paola Murgas, Patricio Manque, Ute Woehlbier, Claudia Duran-Aniotz, Claudio Hetz, María Isabel Behrens, Carol D. SanMartín, Melissa Nassif *These authors contributed equally to this work.
DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer’s Disease Patients and a Transgenic Model of the Disease
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.
Diego Chaparro, Areli Flores-Gaspar, Jorge Alí-Torres
Computational Design of Copper Ligands with Controlled Metal Chelating, Pharmacokinetics, and Redox Properties for Alzheimer’s Disease
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.
Daniel Cuervo-Zanatta, Jaime Garcia-Mena, Claudia Perez-Cruz
Gut Microbiota Alterations and Cognitive Impairment Are Sexually Dissociated in a Transgenic Mice Model of Alzheimer’s Disease
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.
Cindy Santiago-Castañeda, Marysol Segovia-Oropeza, Luis Concha, Sandra Adela Orozco-Suárez, Luisa Rocha
Propylparaben Reduces the Long-Term Consequences in Hippocampus Induced by Traumatic Brain Injury in Rats: Its Implications as Therapeutic Strategy to Prevent Neurodegenerative Diseases
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.
Julio A. Flores-Cuadra, Alanna Madrid, Patricia L. Fernández, Ambar R. Pérez-Lao, Diana C. Oviedo, Gabrielle B. Britton, Maria B. Carreira
Critical Review of the Alzheimer’s Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?
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.
Mario Gil, Ney Alliey-Rodriguez, Juan Carlos Lopez-Alvarenga, Vincent Diego, Ciro A. Gaona, Ledys Mata, Rosa V. Pirela, Carlos A. Chavez, Gabriel A. de Erausquin, Jesus D. Melgarejo, Gladys E. Maestre
Neuropsychiatric Symptoms Among Hispanics: Results of the Maracaibo Aging Study
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 above of 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.
Fernando Castro, Jesús Melgarejo, Carlos A. Chavez, Gabriel A. de Erausquin, Joseph D. Terwilliger, Joseph H. Lee, Gladys E. Maestre
Total Plasma Homocysteine and Depressive Symptoms in Older Hispanics
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 associate 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. Multivariable 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= 1.62; 95% CI, 1.10-2.21). Conclusion: Elevated levels of tHcy level were associated with depressive symptoms in older Hispanics living under the nutritional and environmental conditions of a developing country.
Tzayaka Castillo-Mendieta, Yoaly Arana-Lechuga, Victoria Campos-Peña, Ana Luisa Sosa, Sandra Orozco-Suarez, Rodolfo Pinto-Almazán, Julia Segura-Uribe, Aldo Javier Rodríguez-Sánchez de Tagle, Elizabeth Ruiz-Sánchez, Christian Guerra-Araiza
Plasma Levels of Amyloid-β Peptides and Tau Protein in Mexican Patients with Alzheimer’s Disease
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 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.
Nohela B. Arévalo, Daniela P. Castillo-Godoy, Italo Espinoza-Fuenzalida, Nicole K. Rogers, Gonzalo Farias, Carolina Delgado, Mauricio Henriquez, Luisa Herrera, María Isabel Behrens, Carol D. SanMartín
Association of Vitamin D Receptor Polymorphisms with Amyloid-β Transporters Expression and Risk of Mild Cognitive Impairment in a Chilean Cohort
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.
Carlos Ayala-Grosso, Fátima Torrico, Margot Ledezma-Ruiz, Maria Busolo-Pons
Chronic Stress in Cognitive Processes: Cortisol Dynamic Range of Secretion Is Associated with Perception of Unsafety Environment in a Venezuelan Population
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 detected and 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.
Diana C. Oviedo, Ambar R. Perez-Lao, Julio A. Flores-Cuadra, Alcibiades E. Villarreal, Maria B. Carreira, Shantal A. Grajales, Gabrielle B. Britton
Apolipoprotein ε4 Affects Multiple Domains of Neuropsychological Functioning in a Sample of Elderly Hispanics
Abstract: Apolipoprotein ε4 allele (APOE ε4) 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 ε4 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 ε4 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 ε4 and impairment in specific cognitive domains in elderly Hispanics.
Adrian Orjuela*, Johant Lakey-Beitia*, Randy Mojica-Flores, Muralidhar L. Hegde, Isaias Lans, Jorge Alí-Torres, K.S. Rao *These authors contributed equally to this work.
Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-β Monomers and Fibrils: Relevance to Alzheimer’s Disease
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.
Johant Lakey-Beitia, Andrea M. Burillo, Giovanni La Penna, Muralidhar L. Hegde, K.S. Rao
Polyphenols as Potential Metal Chelation Compounds Against Alzheimer’s Disease
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.
Viviana Soto-Mercado, Miguel Mendivil-Perez, Marlene Jimenez-Del-Rio, Carlos Velez-Pardo
Multi-Target Effects of the Cannabinoid CP55940 on Familial Alzheimer’s Disease PSEN1 E280A Cholinergic-Like Neurons: Role of CB1 Receptor
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 (1 µM) only or in the presence of the CB1 and CB2 receptors (CB1Rs, CB2Rs) inverse agonist SR141716 (1 µM) and SR144528 (1 µM) 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 ΔΨm, decreases oxidation of DJ-1Cys106-SH residue, and blocks the activation of c-Jun, p53, PUMA, and caspase-3 independently of CB1Rs signaling in mutant ChLNs. CP also inhibits the generation of reactive oxygen species partially dependent on CB1Rs. 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, CB1Rs inverse agonists, and anti-Aβ antibodies might be a promising therapeutic approach for the treatment of familial AD.
Agustin Ibanez, Mario A Parra, Christopher Butler for The Latin America and the Caribbean Consortium on Dementia (LAC-CD)
The Latin America and the Caribbean Consortium on Dementia (LAC-CD): From Networking to Research to Implementation Science
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.