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

Authors: Rao, K.S. Jagannatha | Britton, Gabrielle B. | Rocha Arrieta, Luisa Lilia | Garcia-Cairasco, Norberto | Lazarowski, Alberto | Palacios, Adrián | Camins Espuny, Antoni | Maccioni, Ricardo B.

Article Type: Introduction

DOI: 10.3233/JAD-210245

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S1-S4, 2021

Authors: Araya-Arriagada, Joaquín | Bello, Felipe | Shivashankar, Gaganashree | Neira, David | Durán-Aniotz, Claudia | Acosta, Mónica L. | Escobar, María José | Hetz, Claudio | Chacón, Max | Palacios, Adrián G.

Article Type: Research Article

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. Show more

Keywords: Alzheimer’s disease, GABA, glutamate, retinal ganglion cells, 5xFAD transgenic mice

DOI: 10.3233/JAD-201195

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S5-S18, 2021

Authors: Martínez-García, Ignacio | Hernández-Soto, Rebeca | Villasana-Salazar, Benjamín | Ordaz, Benito | Peña-Ortega, Fernando

Article Type: Research Article

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 peptide (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 needs further exploration. 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 slices. 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 slices. 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. Show more

Keywords: Alzheimer’s disease, coherence, hyperexcitability, local field potential, main olfactory bulb, olfactory function, piriform cortex

DOI: 10.3233/JAD-201392

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S19-S35, 2021

Authors: Mercerón-Martínez, Daymara | Ibaceta-González, Cristobal | Salazar, Claudia | Almaguer-Melian, William | Bergado-Rosado, Jorge A. | Palacios, Adrian G.

Article Type: Review Article

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. Show more

Keywords: Neural plasticity, neurorestauration, non-transgenic animal models of neurodegeneration

DOI: 10.3233/JAD-201178

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S37-S50, 2021

Authors: Guzman-Martinez, Leonardo | Calfío, Camila | Farias, Gonzalo A. | Vilches, Cristian | Prieto, Raul | Maccioni, Ricardo B.

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, biomarkers, early detection, meditation, non-pharmacological treatment, nutraceutical compounds, prevention, Traditional Chinese Medicine, Qigong and Taijiquan

DOI: 10.3233/JAD-201059

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S51-S63, 2021

Authors: Hüttenrauch, Melanie | Lopez-Noguerola, José Sócrates | Castro-Obregón, Susana

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, dementia, mind-body therapy, mild cognitive impairment, meditation, yoga

DOI: 10.3233/JAD-200743

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S65-S90, 2021

Authors: Ettcheto, Miren | Busquets, Oriol | Cano, Amanda | Sánchez-Lopez, Elena | Manzine, Patricia R. | Espinosa-Jimenez, Triana | Verdaguer, Ester | Sureda, Francesc X. | Olloquequi, Jordi | Castro-Torres, Ruben D. | Auladell, Carme | Folch, Jaume | Casadesús, Gemma | Camins, Antoni

Article Type: Review Article

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 slowdown 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. Show more

Keywords: BDNF, dendritic spines, late onset Alzheimer’s disease, neuroinflammation, obesity, type 2 diabetes mellitus

DOI: 10.3233/JAD-201106

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S91-S107, 2021

Authors: Merelli, Amalia | Repetto, Marisa | Lazarowski, Alberto | Auzmendi, Jerónimo

Article Type: Review Article

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. Show more

Keywords: ABC-transporters, erythropoietin, Fe/Cu, HIF-1α, hypoxia, inflammation, neurodegeneration, oxidative stress

DOI: 10.3233/JAD-201074

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S109-S126, 2021

Authors: Busquets, Oriol | Parcerisas, Antoni | Verdaguer, Ester | Ettcheto, Miren | Camins, Antoni | Beas-Zarate, Carlos | Castro-Torres, Rubén Darío | Auladell, Carme

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, amyloid-β, axonal transport, hyperphosphorylated tau, JNK, synapse loss

DOI: 10.3233/JAD-201053

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S127-S139, 2021

Authors: Posada-Duque, Rafael Andrés | Cardona-Gómez, Gloria Patricia

Article Type: Review Article

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. Show more

Keywords: Alzheimer’s disease, astrocytes, CDK5, endothelium, neuroprotection, neurovascular unit

DOI: 10.3233/JAD-200730

Citation: Journal of Alzheimer's Disease, vol. 82, no. s1, pp. S141-S161, 2021