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Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as ß-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-ß clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.
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Background: There is a common agreement that Alzheimers disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Objective: To perform a scoping review of original manuscripts describing hypotheses and theories of AD published in the past decades. Results: We reviewed 131 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases. Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools. Results: Three stages can be discerned in terms of hypotheses generation, with three quarter of studies proposing a hypothesis characterized as being single-focus. The most important theoretical groupings were the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infections and Cerebrovascular. Lately, evidence towards Genetics and especially Gut/Brain interactions came to the fore. Conclusions: When viewed together, these multi-faceted reports reinforce the notion that AD affects multiple sub-cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. The challenge of providing a comprehensive view of all systems and their interactions remains, alongside ways to manage this inherent complexity.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Encéfalo/patologiaRESUMO
Alzheimer's disease (AD) is a fatal neurological illness that worsens with time. Preventing the aggregate formation of amyloid beta protein is a promising approach to treat Alzheimer's disease. This article describes an amiable procedure for the synthesis of Olesoxime-Resveratrol (OLX-RSV) encapsulated in exosomes. By suppressing Aß1-42 aggregation and crossing the blood-brain barrier also known as BBB after intravenous treatment without resulting in any discernible damage, the nanocomposite demonstrated good biocompatibility. A variety of characterization technique including particle size, TEM, and in vitro drug release experiments, were used to characterize the exosomes. Human Neuroblastoma (SHSY5Y) cells were used to test the cytotoxicity and viability of cells of the formulation using the Cell Counting Kit-8 assay. The prepared OLX-RSV-loaded exosomes were tested for their ability to suppress Aß1-42 in SHSY5Y Cells by analyzing the amyloid samples using CD spectra. The effects of apoptosis on Human neuroblastoma cells were studied using cytofluorometry. The parameters of SOD, caspase-3 and the ability to scavenge reactive oxygen species (ROS) were also evaluated. The behavioral outcomes of Morris water maze test demonstrated that OLX-RSV-loaded exosomes significantly enhanced the APP/PS1 mice's capacity to learn and remember spatial cues. Therefore, we hypothesized that OLX-RSV-loaded exosomes could be a useful and efficient method in the treatment of AD.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Cognição , Modelos Animais de Doenças , Exossomos , Resveratrol , Animais , Resveratrol/farmacologia , Resveratrol/administração & dosagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Exossomos/metabolismo , Humanos , Camundongos , Linhagem Celular Tumoral , Cognição/efeitos dos fármacos , Cognição/fisiologia , Fragmentos de Peptídeos/farmacologia , Apoptose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Masculino , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/efeitos dos fármacosRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory impairment, a loss of cholinergic neurons, and cognitive decline that insidiously progresses to dementia. The pathoetiology of AD is complex, as genetic predisposition, age, inflammation, oxidative stress, and dysregulated proteostasis all contribute to its development and progression. The histological hallmarks of AD are the formation and accumulation of amyloid-ß plaques and interfibrillar tau tangles within the central nervous system. These histological hallmarks trigger neuroinflammation and disrupt the physiological structure and functioning of neurons, leading to cognitive dysfunction. Most treatments currently available for AD focus only on symptomatic relief. Disease-modifying treatments (DMTs) that target the biology of the disease in hopes of slowing or reversing disease progression are desperately needed. This narrative review investigates novel DMTs and their therapeutic targets that are either in phase three of development or have been recently approved by the U.S. Food and Drug Administration (FDA). The target areas of some of these novel DMTs consist of combatting amyloid or tau accumulation, oxidative stress, neuroinflammation, and dysregulated proteostasis, metabolism, or circadian rhythm. Neuroprotection and neuroplasticity promotion were also key target areas. DMT therapeutic target diversity may permit improved therapeutic responses in certain subpopulations of AD, particularly if the therapeutic target of the DMT being administered aligns with the subpopulation's most prominent pathological findings. Clinicians should be cognizant of how these novel drugs differ in therapeutic targets, as this knowledge may potentially enhance the level of care they can provide to AD patients in the future.
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OBJECTIVES: In this study, we examine the measurement of cognition in different racial/ethnic groups to move towards a less biased and more inclusive set of measures for capturing cognitive change and decline in older adulthood. METHODS: We use data from Round 2 (N=3377) and Round 3 (N=4777) of the National Social Life, Health, and Aging Project (NSHAP) and examine the study's Survey Adjusted version of the Montreal Cognitive Assessment (MoCA-SA). We employ exploratory factor analyses to explore configural invariance by racial/ethnic group. Using modification indexes, two-parameter item response theory models, and split-sample testing, we identify items that seem robust to bias by race. We test the predictive validity of the full (18-item) and short (4-item) MoCA-SAs using self-reported dementia diagnosis, instrumental activities of daily living (IADLs), proxy reports of dementia, proxy reports of dementia-related death, and National Death Index reports of dementia-related death. RESULTS: We found that four measures out of the 18 used in NSHAP's MoCA-SA formed a scale that was more robust to racial bias. The shortened form predicted consequential outcomes as well as NSHAP's full MoCA-SA. The short form was also moderately correlated with the full form. DISCUSSION: Although sophisticated structural equation modeling techniques would be preferrable for assuaging measurement invariance by race in NSHAP, the shortened form of the MoCA-SA provides a quick way for researchers to carry out robustness checks and to see if the disparities and associations by race they document are "real" or the product of artifactual bias.
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Several in vivo studies have shown that systemic inflammation, mimicked by LPS, triggers an inflammatory response in the CNS, driven by microglia, characterized by an increase in inflammatory cytokines and associated sickness behavior. However, most studies induce relatively high systemic inflammation, not directly compared with the more common low-grade inflammatory events experienced in humans during the life course. Using mice, we investigated the effects of low-grade systemic inflammation during an otherwise healthy early life, and how this may precondition the onset and severity of Alzheimer's disease (AD)-like pathology. Our results indicate that low-grade systemic inflammation induces sub-threshold brain inflammation and promotes microglial proliferation driven by the CSF1R pathway, contrary to the effects caused by high systemic inflammation. In addition, repeated systemic challenges with low-grade LPS induce disease-associated microglia. Finally, using an inducible model of AD-like pathology (Line 102 mice), we observed that preconditioning with repeated doses of low-grade systemic inflammation, prior to APP induction, promotes a detrimental effect later in life, leading to an increase in Aß accumulation and disease-associated microglia. These results support the notion that episodic low-grade systemic inflammation has the potential to influence the onset and severity of age-related neurological disorders, such as AD.
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Doença de Alzheimer , Inflamação , Lipopolissacarídeos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microglia , Animais , Microglia/metabolismo , Microglia/patologia , Doença de Alzheimer/patologia , Doença de Alzheimer/metabolismo , Inflamação/patologia , Inflamação/metabolismo , Lipopolissacarídeos/farmacologia , Camundongos , Modelos Animais de Doenças , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Masculino , Feminino , Precursor de Proteína beta-Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/genética , Encéfalo/patologia , Encéfalo/metabolismo , Peptídeos beta-Amiloides/metabolismo , Citocinas/metabolismoRESUMO
Alzheimer's disease (AD) is a significant 21st-century public health challenge. This article delves into AD's neurodegenerative complexities, highlighting cognitive decline, memory impairment, and societal burdens. Mechanistically, protein misfolding, amyloid-beta (Aß) pathway abnormalities, and genetic/environmental factors are discussed. The pivotal amyloid hypothesis is dissected, focusing on Aß aggregation's role in synaptic dysfunction and neurodegeneration. The review showcases promising therapeutic strategies, including anti-amyloid antibodies and ß/γ-secretase inhibitors targeting Aß production. Notably, the FDA-approved Lecanemab signifies a breakthrough, slowing disease progression. Anti-Tau therapies' emergence is highlighted, addressing late-stage intervention. Tau aggregation blockers and anti-Tau antibodies offer potential against intracellular tau pathology. The review underscores collaborative efforts to uncover AD's secrets and pave the way for memory preservation.
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This scientific commentary refers to 'Inhibition of insulin-degrading enzyme in human neurons promotes amyloid-ß deposition' by Rowland et al. (https://doi.org/10.1042/NS20230016). Insulin-degrading enzyme (IDE) and neprilysin (NEP) have been proposed as two Aß-degrading enzymes supported by human genetics and in vivo data. Rowland et al. provide complementary evidence of a key role for IDE in Aß metabolism in human-induced pluripotent stem cell (iPSC)-derived cortical neurons.
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BACKGROUND: Exercise is postulated to be a promising non-pharmacological intervention for the improvement of neurodegenerative disease pathology. However, the mechanism of beneficial effects of exercise on the brain remains to be further explored. In this study, we investigated the effect of an exercise-induced metabolite, lactate, on the microglia phenotype and its association with learning and memory. RESULTS: Microglia were hyperactivated in the brains of AlCl3/D-gal-treated mice, which was associated with cognitive decline. Running exercise ameliorated the hyperactivation and increased the anti-inflammatory/reparative phenotype of microglia and improved cognition. Mice were injected intraperitoneally with sodium lactate (NaLA) had similar beneficial effects as that of exercise training. Exogenous NaLA addition to cultured BV2 cells promoted their transition from a pro-inflammatory to a reparative phenotype. CONCLUSION: The elevated lactate acted as an "accelerator" of the endogenous "lactate timer" in microglia promoting this transition of microglia polarization balance through lactylation. These findings demonstrate that exercise-induced lactate accelerates the phenotypic transition of microglia, which plays a key role in reducing neuroinflammation and improving cognitive function.
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Alzheimer's disease (AD) is characterised by the aggregation and deposition of amyloid-ß (Aß) peptides in the human brain. In age-related late-onset AD, deficient degradation and clearance, rather than enhanced production, of Aß contributes to disease pathology. In the present study, we assessed the contribution of the two key Aß-degrading zinc metalloproteases, insulin-degrading enzyme (IDE) and neprilysin (NEP), to Aß degradation in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Using an Aß fluorescence polarisation assay, inhibition of IDE but not of NEP, blocked the degradation of Aß by human neurons. When the neurons were grown in a 3D extracellular matrix to visualise Aß deposition, inhibition of IDE but not NEP, increased the number of Aß deposits. The resulting Aß deposits were stained with the conformation-dependent, anti-amyloid antibodies A11 and OC that recognise Aß aggregates in the human AD brain. Inhibition of the Aß-forming ß-secretase prevented the formation of the IDE-inhibited Aß deposits. These data indicate that inhibition of IDE in live human neurons grown in a 3D matrix increased the deposition of Aß derived from the proteolytic cleavage of the amyloid precursor protein. This work has implications for strategies aimed at enhancing IDE activity to promote Aß degradation in AD.
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OBJECTIVES: The proportion of older people with dementia in China is gradually increasing with the increase in the aging population over recent years. Hypertension and diabetes are common non-communicable diseases among rural populations in China. However, it remains unclear whether these conditions affect the occurrence and development of cognitive impairment as there is limited research on cognitive status and its risk factors among residents of rural areas. METHODS: A multi-stage stratified cluster random sampling method was used to select 5400 participants from rural permanent residents. A self-designed structured questionnaire was used to investigate demographic data of the participants. Cognitive function was assessed using the Montreal Cognitive Function Assessment Scale (MoCA). The results were analyzed using chi-square test, ANOVA and multiple linear regression analysis. RESULTS: A total of 5028 participants returned the survey, giving a response rate of 93.1%. Higher education (odds ratio (OR) = 3.2, 95% confidence interval (CI) 2.87-3.54, p < 0.001), higher income (OR = 1.61, 95% CI 1.16-2.07, p < 0.001), and dietary control (OR = 0.66, 95%CI 0.34-0.98, p < 0.001) were protective factors. A visual representation of the relationship between annual income and MoCA score showed an inverted U-curve, the group with an annual income of 6000-7999 RMB had a maximum OR of 1.93 (95%CI 0.12-2.74, p < 0.001). While difficulty in maintaining sleep were risk factors for cognitive impairment (OR = -2.28, 95% CI-4.18-0.39, p = 0.018). CONCLUSIONS: Participants with middle incomes had better cognitive status than those with the highest incomes. Higher education, proper diet control and good sleep are beneficial to the cognitive status of residents in rural areas.
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Diabetes Mellitus , Hipertensão , Humanos , Idoso , Estudos Transversais , População Rural , Fatores de Risco , Hipertensão/epidemiologia , Cognição , China/epidemiologiaRESUMO
BACKGROUND: The primary aim of the current pilot study was to examine enrollment rate, data completion, usability, acceptance and use of a mobile telehealth application, Brain CareNotes. A secondary aim was to estimate the application's effect in reducing caregiver burden and behavioral and psychological symptoms related to dementia (BPSD). METHODS: Patient-caregiver dyads (n = 53) were recruited and randomized to intervention and control groups. Assessment of usability, acceptance, BPSD symptoms, and caregiver burden were collected at baseline, 3- and 6-month follow-up. RESULTS: The enrollment rate was acceptable despite pandemic related challenges (53/60 target recruitment sample). Among randomized individuals, there was a retention rate of 85% and data completion was attained for 81.5% of those allocated to usual care and 88.5% of those allocated to Brain CareNotes. Mean caregiver-reported app usability at 6 months was 72.5 (IQR 70.0-90.0) on the System Usability Scale-considered "Good to Excellent"-and user acceptance was reasonable as indicated by 85%-90% of caregivers reporting they would intend to use the app to some degree in the next 6 months, if able. Regarding intervention effect, although differences in outcome measures between the groups were not statistically significant, compared to baseline, we found a reduction of caregiver burden (NPI-Caregiver Distress) of 1.0 at 3 months and 0.7 at 6 months for those in the intervention group. BPSD (NPI Total Score) was also reduced from baseline by 4.0 at 3 months and by 0.5 at 6 months. CONCLUSIONS: Brain CareNotes is a highly scalable, usable and acceptable mobile caregiver intervention. Future studies should focus on testing Brain CareNotes on a larger sample size to examine efficacy of reducing caregiver burden and BPSD.
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Doença de Alzheimer , Demência , Humanos , Doença de Alzheimer/terapia , Doença de Alzheimer/psicologia , Cuidadores/psicologia , Demência/psicologia , Estudos de Viabilidade , Projetos Piloto , EncéfaloRESUMO
The complete cessation of menstruation for 12 months with associated vasomotor symptoms is termed menopause. Apart from playing a role in reproduction, estrogen significantly affects the central nervous system (CNS). Population-based studies highlighted a substantial difference in the prevalence of dementia between men and women, with Alzheimer-associated dementia being more prevalent in women, indicating that estrogen deficiency might be a risk factor for neurodegenerative diseases. Patients with dementia experience a progressive decline in neurocognitive function, beginning with short-term memory loss that progresses to long-term memory loss and the inability to perform everyday activities, leading ultimately to death. There is currently no cure for dementia, so preventing or slowing the disease's progression is paramount. Accordingly, researchers have widely studied the role of estrogen as a neuroprotective agent. Estrogen prevents dementia by augmenting Hippocampal and prefrontal cortex function, reducing neuroinflammation, preventing degradation of estrogen receptors, decreasing oxidative damage to the brain, and increasing cholinergic and serotonergic function. According to the window phase hypothesis, estrogen's effect on preventing dementia is more pronounced if therapy is started early, during the first five years of menopause. Other studies like The Woman's Health Initiative Memory Study (WHIMS) showed unfavorable effects of estrogen on the brain. This review aims to establish an understanding of the currently available data on estrogen's effect on neurodegeneration, namely, dementia and Alzheimer's disease.
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Asthma and brain interactions have long been appreciated and initially centered on increased anxiety and depression. Epidemiology studies have shown that early life stressors and situational disadvantages are risk factors for asthma. Conversely, the presence of asthma is a risk for mood and anxiety disorders, thus indicating a bidirectional effect between asthma and brain-related health. To substantiate asthma-brain interactions, validated instruments indicate and elucidate that communication likely exists between asthma and the brain. For example, provocation of an asthmatic response with an allergen challenge modulates how the brain responds to emotion-laden information. As detected by imaging studies, emotion-related brain activation is associated with generating airway inflammation. However, the specific mediators and processes mediating airway communication with the brain have yet to be established.Systemic inflammation is also associated with asthma and can affect other organ systems such as the cardiovascular system and the brain. Epidemiology studies have shown that asthma is a risk factor for dementia and Alzheimer's disease. In support of the importance of asthma as a risk factor for impaired cognitive function, imaging studies have shown changes to the white matter of the brain in asthma patients that resemble neuroinflammation changes seen in Alzheimer's disease and other neurodegenerative diseases. Therefore, bidirectional links between asthma and the brain exist with an important next research step to define asthma-brain interactions linked to neurodegeneration and dementia and explore whether treatments directed toward asthma-related inflammation can prevent the deleterious effects of asthma on brain health.
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Doença de Alzheimer , Asma , Humanos , Sistema Respiratório , Inflamação , EncéfaloRESUMO
Clearance of Alzheimer's amyloid oligomers from the brain is crucial for preventing cell toxicity. Dementia complications arise as a result of apoptosis, which is caused by peptide plaques on the lipid surface of cells. Here, we employed all-atom and coarse-grained molecular dynamics simulations to investigate the aggregation of amyloid peptides at the lipid surface and the role of aquaporin-4 (AQP4) in facilitating peptide clearance from astrocytes. The network of protein-protein interactions through text mining revealed that the expression of AQP4 and amyloid aggregation were strongly correlated. It has also been revealed that the role of aquaporins in the etiology of Alzheimer's disease involves several interconnected proteins and pathways. The nature of aggregation at the surface of the 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) lipid bilayer was revealed by the interaction of amyloid oligomers. The membrane-bound pore region of AQP4 interacts with the peptide and slows its aggregation. This interaction maintains the helical content of the peptide while lowering its toxicity at the lipid surface. The hydrophobicity of the peptide also decreased because of these interactions, which may help in the removal of the peptide from astrocytes. Long-term coarse-grained MD simulations demonstrated different features of oligomer aggregation at the surface and strong oligomer attraction to AQP4, which inhibited aggregation. Additionally, the water dynamics of aquaporins demonstrate how the selectivity filter is broken to disrupt water flow. Our findings also provide insight into the physiological alterations in brain tissue associated with Alzheimer's disease, including water retention and increased water flow in the CSF. Furthermore, in vitro thioflavin fluorescence spectroscopy revealed a slower aggregation of the peptide in the presence of AQP4.
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Doença de Alzheimer , Aquaporinas , Humanos , Peptídeos beta-Amiloides/metabolismo , Doença de Alzheimer/metabolismo , Bicamadas Lipídicas/metabolismo , Simulação de Dinâmica Molecular , Aquaporinas/metabolismo , Amiloide/metabolismo , Água/química , Fragmentos de Peptídeos/metabolismoRESUMO
BACKGROUND: The continuum of Alzheimer's disease (AD) comprises three stages: the pre-clinical stage (with few to no subjective symptoms), the prodromal stage (measurable mild cognitive impairment) and the final stage of clinically manifest (AD) dementia. Neuropathological correlates in accordance with these stages have been found with varying frequency. The aim of early AD diagnosis is to determine such correlates in these preclinical and prodromal stages and to determine the probability of the manifestation of a later AD dementia. In this regard, the prognostic validity is of vital importance. From the perspective of those affected, the issue of early diagnosis cannot be reduced to AD, although Alzheimer's dementia is by far the most common form of dementia. The aim of this review is to provide a literature-based overview of the advantages and disadvantages of early AD diagnosis in contrast to other types of dementia. Based on this, recommendations will be formulated for the prioritisation of early diagnostic advantages and disadvantages in the patient counselling situation in clinical practice. METHODS: Three databases were searched for current reviews addressing the advantages, disadvantages and ethical aspects of early AD diagnosis. The search was limited to current German or English reviews published between January 1, 2018 and November 30, 2022. The systematic search strategy was based on the PICO model and included both a Boolean and a focus-expanding keyword search using previously defined search terms. In addition, snowballing was used as a search strategy. Qualitative synoptic content analysis in accordance with Mayring was used to analyse both advantages and disadvantages. Similar arguments were combined into single statements. The resulting statements were categorized into three main groups: social, individual or clinical aspects. To emphasize the aforementioned aims, arguments were additionally distinguished into "only valid for early AD diagnosis" and "valid for early diagnosis of all types of dementia". RESULTS: Overall, seven reviews with suitable content were included. Social aspects of early AD diagnosis comprise the protection of the affected person and the society as well as potential stigmatisation of the affected and their family members. Individual arguments range from the right to a "rational suicide", including the avoidance of financial and caregiving burdens on family members, to the right not to know the diagnosis. Clinical arguments include, for example, the scientific research context (facilitating the identification of suitable clinical trial participants) and various negative effects of a false positive or false negative early diagnosis. CONCLUSION: Early diagnosis of AD as well as of other forms of dementia is characterised by numerous advantages and disadvantages of a social, individual and clinical nature. The decision for or against early diagnosis should always be made by weighing the current advantages against the disadvantages in a specific case. In particular, the desires of the person affected, the validity of the diagnostic procedures available and, above all, the availability of effective preventive or therapeutic measures must be taken into account.
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Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Alemanha , Disfunção Cognitiva/diagnóstico , Diagnóstico Precoce , Sensibilidade e EspecificidadeRESUMO
Alzheimer's disease (AD) is characterized by complex etiology, long-lasting pathogenesis, and cell-type-specific alterations. Currently, there is no cure for AD, emphasizing the urgent need for a comprehensive understanding of cell-specific pathology. Astrocytes, principal homeostatic cells of the central nervous system, are key players in the pathogenesis of neurodegenerative diseases, including AD. Cellular models greatly facilitate the investigation of cell-specific pathological alterations and the dissection of molecular mechanisms and pathways. Tumor-derived and immortalized astrocytic cell lines, alongside the emerging technology of adult induced pluripotent stem cells, are widely used to study cellular dysfunction in AD. Surprisingly, no stable cell lines were available from genetic mouse AD models. Recently, we established immortalized hippocampal astroglial cell lines from amyloid-ß precursor protein/presenilin-1/Tau triple-transgenic (3xTg)-AD mice (denominated as wild type (WT)- and 3Tg-iAstro cells) using retrovirus-mediated transduction of simian virus 40 large T-antigen and propagation without clonal selection, thereby maintaining natural heterogeneity of primary cultures. Several groups have successfully used 3Tg-iAstro cells for single-cell and omics approaches to study astrocytic AD-related alterations of calcium signaling, mitochondrial dysfunctions, disproteostasis, altered homeostatic and signaling support to neurons, and blood-brain barrier models. Here we provide a comparative overview of the most used models to study astrocytes in vitro, such as primary culture, tumor-derived cell lines, immortalized astroglial cell lines, and induced pluripotent stem cell-derived astrocytes. We conclude that immortalized WT- and 3Tg-iAstro cells provide a non-competitive but complementary, low-cost, easy-to-handle, and versatile cellular model for dissection of astrocyte-specific AD-related alterations and preclinical drug discovery.
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The medicinal properties of cannabis and cannabinoid-derivative are entirely investigated and known. In addition, the identification of psychotropic plant cannabinoids has led to more studies regarding the cannabinoid system and its therapeutic features in the treatment and management of clinical symptoms of neuroinflammatory disorders, such as multiple sclerosis (MS), Parkinsons disease (PD), and Alzheimers disease (AD). In fact, cannabinoid agonists are able to control and regulate inflammatory responses. In contrast to the cannabinoid receptor type 1 (CB1) and its unwanted adverse effects, the cannabinoid receptor type 2 (CB2) and its ligands hold promise for new and effective therapeutic approaches. So far, some successes have been achieved in this field. This review will discuss an outline of the endocannabinoid system's involvement in neuroinflammatory disorders. Moreover, the pharmacological efficacy of different natural and synthetic preparations of phytocannabinoids acting on cannabinoid receptors, particularly in MS, PD, and AD, will be updated. Also, the reasons for targeting CB2 for neurodegeneration will be explained.
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Doença de Alzheimer , Canabinoides , Esclerose Múltipla , Doença de Parkinson , Humanos , Canabinoides/uso terapêutico , Canabinoides/farmacologia , Esclerose Múltipla/tratamento farmacológico , Doenças Neuroinflamatórias , Doença de Alzheimer/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Endocanabinoides , Receptores de CanabinoidesRESUMO
The amyloid hypothesis, which proposes that accumulation of the peptide amyloid-ß at synapses is the key driver of Alzheimer's disease (AD) pathogenesis, has been the dominant idea in the field of Alzheimer's research for nearly 30 years. Recently, however, serious doubts about its validity have emerged, largely motivated by disappointing results from anti-amyloid therapeutics in clinical trials. As a result, much of the AD research effort has shifted to understanding the roles of a variety of other entities implicated in pathogenesis, such as microglia, astrocytes, apolipoprotein E and several others. All undoubtedly play an important role, but the nature of this has in many cases remained unclear, partly due to their pleiotropic functions. Here, we propose that all of these AD-related entities share at least one overlapping function, which is the local regulation of amyloid-ß levels, and that this may be critical to their role in AD pathogenesis. We also review what is currently known of the actions of amyloid-ß at the synapse in health and disease, and consider in particular how it might interact with the key AD-associated protein tau in the disease setting. There is much compelling evidence in support of the amyloid hypothesis; rather than detract from this, the implication of many disparate AD-associated cell types, molecules and processes in the regulation of amyloid-ß levels may lend further support.