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1.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 41(5): 702-708, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31699204

RESUMO

Alzheimer's disease(AD)is a central nervous system disease characterized by progressive cognitive dysfunction and memory loss.Increasing evidences suggest that ß amyloid(Aß)plays a critical role and may be a upstream molecule in AD pathogenesis involving both genetic and environmental factors.Aß accumulation and its related inflammation are considered early events preceding neurodegeneration and neuronal loss in AD brain.However,all strategies and compounds targeting Aß deposition have failed in clinical trials,implying complexity of AD pathogenesis.This article reviews Aß hypothesis and its related mechanisms,pathophysiological process,and therapeutics of AD.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Doença de Alzheimer/prevenção & controle , Doença de Alzheimer/terapia , Encéfalo/fisiopatologia , Humanos
2.
Brain Nerve ; 71(10): 1081-1088, 2019 Oct.
Artigo em Japonês | MEDLINE | ID: mdl-31588052

RESUMO

During the past 20 years, genome studies for Alzheimer's disease (AD) have elucidated the pathogenesis of AD including the amyloid hypothesis. However, clinical trials of the disease modifying drugs for AD developed based on the amyloid hypothesis have been largely unsuccessful. New genes associated with AD have been identified through comprehensive genome analyses such as genome-wide association studies and whole genome/exome sequencing using next-generation sequencers. With these efforts, new therapeutic targets to AD have been explored. This review summarizes the genetic make-up of AD in terms of both risk and protective factors from the viewpoint of novel therapeutic targets to AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/terapia , Testes Genéticos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Fatores de Proteção , Fatores de Risco
3.
Medicine (Baltimore) ; 98(42): e17557, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31626119

RESUMO

BACKGROUND: Mild cognitive impairment (MCI) and Alzheimer's disease (AD) are neurodegenerative diseases associated with aging. The major clinical features of both are progressive memory loss and progressive cognitive loss. The objective of this systematic review protocol is to provide the methods for evaluating the effectiveness of acupuncture in the treatment on cognitive deficits in transgenic mouse. METHODS AND ANALYSIS: We will search the electronic databases of PubMed, Web of Science, Embase, PsycINFO, as well as the Chinese databases such as Chinese Biomedicine Literature (CBM), Chinese Medical Current Content (CMCC), Chinese Scientific Journal Database (VIP), WanFang Database and China National Knowledge Infrastructure (CNKI) from their inceptions to July 2019. RevMan 5.3 software will be used for the data synthesis and the quality of each study was assessed independently by use of the CAMARADES checklist. RESULTS: This review will provide a high-quality synthesis based on present evidence of acupuncture treatment for AD and MCI in transgenic mouse models. CONCLUSIONS: This systematic review will provide evidence for weather acupuncture is an effective intervention for AD and MCI in transgenic mouse models. ETHICS AND DISSEMINATION: Ethical approval is not necessary since this protocol is only for systematic review and does not involve privacy data or conduct an animal experiment. This protocol will be disseminated by a peer-review journal or conference presentation. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019142985. STRENGTHS AND LIMITATIONS OF THIS STUDY: This systematic review will be the first to provide new knowledge underlying the effectiveness to improve cognitive function of acupuncture treatment for AD and MCI in transgenic mouse models. The result of this systematic review may provide experimental and theoretical basis for the future clinical application of acupuncture in the treatment of AD.The limitation of this systematic review may come from language barriers, because only English and Chinese can be included. Also, this study includes various kinds of acupuncture treatments which may result in essential heterogeneity.


Assuntos
Terapia por Acupuntura/métodos , Doença de Alzheimer/terapia , Cognição/fisiologia , Disfunção Cognitiva/terapia , Doença de Alzheimer/complicações , Doença de Alzheimer/fisiopatologia , Animais , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos
4.
JAMA ; 322(16): 1589-1599, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31638686

RESUMO

Importance: Worldwide, 47 million people live with dementia and, by 2050, the number is expected to increase to 131 million. Observations: Dementia is an acquired loss of cognition in multiple cognitive domains sufficiently severe to affect social or occupational function. In the United States, Alzheimer disease, one cause of dementia, affects 5.8 million people. Dementia is commonly associated with more than 1 neuropathology, usually Alzheimer disease with cerebrovascular pathology. Diagnosing dementia requires a history evaluating for cognitive decline and impairment in daily activities, with corroboration from a close friend or family member, in addition to a thorough mental status examination by a clinician to delineate impairments in memory, language, attention, visuospatial cognition such as spatial orientation, executive function, and mood. Brief cognitive impairment screening questionnaires can assist in initiating and organizing the cognitive assessment. However, if the assessment is inconclusive (eg, symptoms present, but normal examination findings), neuropsychological testing can help determine whether dementia is present. Physical examination may help identify the etiology of dementia. For example, focal neurologic abnormalities suggest stroke. Brain neuroimaging may demonstrate structural changes including, but not limited to, focal atrophy, infarcts, and tumor, that may not be identified on physical examination. Additional evaluation with cerebrospinal fluid assays or genetic testing may be considered in atypical dementia cases, such as age of onset younger than 65 years, rapid symptom onset, and/or impairment in multiple cognitive domains but not episodic memory. For treatment, patients may benefit from nonpharmacologic approaches, including cognitively engaging activities such as reading, physical exercise such as walking, and socialization such as family gatherings. Pharmacologic approaches can provide modest symptomatic relief. For Alzheimer disease, this includes an acetylcholinesterase inhibitor such as donepezil for mild to severe dementia, and memantine (used alone or as an add-on therapy) for moderate to severe dementia. Rivastigmine can be used to treat symptomatic Parkinson disease dementia. Conclusions and Relevance: Alzheimer disease currently affects 5.8 million persons in the United States and is a common cause of dementia, which is usually accompanied by other neuropathology, often cerebrovascular disease such as brain infarcts. Causes of dementia can be diagnosed by medical history, cognitive and physical examination, laboratory testing, and brain imaging. Management should include both nonpharmacologic and pharmacologic approaches, although efficacy of available treatments remains limited.


Assuntos
Demência/diagnóstico , Demência/terapia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Inibidores da Colinesterase/efeitos adversos , Inibidores da Colinesterase/uso terapêutico , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Humanos , Memantina/efeitos adversos , Memantina/uso terapêutico , Neuroimagem , Testes Neuropsicológicos
5.
Sr Care Pharm ; 34(9): 600-603, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31601293

RESUMO

Patients with Alzheimer's dementia (AD) often present with behavioral and psychological symptoms of dementia (BPSD), which may include anxiety, depression, and agitation, leading to a decrease in quality of life. Nonpharmacologic methods are recommended as first-line therapy for reducing BPSD. The student chapter of ASCP at Ohio Northern University Raabe College of Pharmacy has partnered with a local nursing facility to implement an active group music therapy (MT) outreach program to assist in management of BPSD. The program also evaluated the perceived effects of this outreach on students. In addition to having a profound impact on the residents, this outreach has also provided an excellent educational outlet for students to establish and practice skills in working with the AD patient population. In this article, we share our experiences with MT and provide education on how to implement MT outreach at your own institution or practice.


Assuntos
Doença de Alzheimer , Musicoterapia , Doença de Alzheimer/terapia , Humanos , Ohio , Qualidade de Vida , Estudantes
6.
Pharm Res ; 36(11): 161, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529284

RESUMO

PURPOSE: Apolipoprotein E2 (ApoE2) gene therapy is a potential disease-modifying therapy for Alzheimer's disease (AD). We investigated the potential of plasmid encoding ApoE2 loaded brain-targeted functionalized-liposomes for treatment of AD. This was achieved via systemic administration of liposomes entrapping therapeutic gene targeting the brain of mice. METHODS: Targeting and transfection efficiency of designed liposomes were determined in bEnd.3, primary glial and primary neuronal cells. The ability of liposomal formulations to translocate across in vitro blood-brain barrier (BBB) and, thereafter, transfect primary neuronal cells was investigated using in vitro triple co-culture BBB model. We quantified ApoE expression in the brain of mice after single intravenous injection of brain-targeted liposomes loaded with plasmid ApoE2. RESULTS: Dual surface modification enhanced the in vitro transfection efficiency of designed liposomes. Successful delivery of therapeutic gene overcoming BBB by Transferrin-Penetratin- modified liposomes was demonstrated both in vitro and in vivo. Significant (p < 0.05) increase in ApoE levels in the brain of mice was observed after intravenous administration of Tf-Pen-liposomes encasing plasmid ApoE2. CONCLUSION: The results indicate that dual-ligand based liposomal gene delivery systems had both enhanced brain targeting and gene delivery efficiencies. Transferrin-Penetratin modified liposomes for delivery of plasmid ApoE2 has great potential for AD treatment.


Assuntos
Apolipoproteína E2/genética , Barreira Hematoencefálica/metabolismo , Terapia Genética , Lipossomos/química , Nanopartículas/química , Doença de Alzheimer/terapia , Animais , Peptídeos Penetradores de Células/química , Peptídeos Penetradores de Células/metabolismo , Feminino , Humanos , Lipossomos/administração & dosagem , Lipossomos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Nanopartículas/metabolismo , Transferrina/química , Transferrina/metabolismo
7.
Clin Interv Aging ; 14: 1243-1254, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31371930

RESUMO

Objective: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the efficacy of cognitive stimulation therapy (CST) of different durations for Alzheimer's disease (AD). Methods: A comprehensive search was carried out in three databases. The primary outcome was Mini-Mental State Examination (MMSE) score. We conducted a meta-analysis with Review Manager, version 5.3 and assessed the methodological quality of the included studies using the Cochrane Collaboration Recommendations assessment tool. Results: Treatment effects from the meta-analysis showed that CST plus acetylcholinesterase inhibitors (ChEIs) was better than the control assessed by MMSE. In addition, the meta-analysis indicated that long-term CST was better than short-term or maintenance CST. Conclusion: Our study confirmed that the combination of CST and drug treatment for AD is effective in AD, regardless of whether short-term CST, maintenance CST, or long-term CST is used. The long-term CST appears to be more effective.


Assuntos
Doença de Alzheimer/terapia , Transtornos Cognitivos/terapia , Terapia Cognitivo-Comportamental/métodos , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Inibidores da Colinesterase/uso terapêutico , Transtornos Cognitivos/etiologia , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento Social
8.
Int J Nanomedicine ; 14: 5541-5554, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31410002

RESUMO

Currently, 47 million people live with dementia globally, and it is estimated to increase more than threefold (~131 million) by 2050. Alzheimer's disease (AD) is one of the major causative factors to induce progressive dementia. AD is a neurodegenerative disease, and its pathogenesis has been attributed to extracellular aggregates of amyloid ß (Aß) plaques and intracellular neurofibrillary tangles made of hyperphosphorylated τ-protein in cortical and limbic areas of the human brain. It is characterized by memory loss and progressive neurocognitive dysfunction. The anomalous processing of APP by ß-secretases and γ-secretases leads to production of Aß40 and Aß42 monomers, which further oligomerize and aggregate into senile plaques. The disease also intensifies through infectious agents like HIV. Additionally, during disease pathogenesis, the presence of high concentrations of Aß peptides in central nervous system initiates microglial infiltration. Upon coming into vicinity of Aß, microglia get activated, endocytose Aß, and contribute toward their clearance via TREM2 surface receptors, simultaneously triggering innate immunoresponse against the aggregation. In addition to a detailed report on causative factors leading to AD, the present review also discusses the current state of the art in AD therapeutics and diagnostics, including labeling and imaging techniques employed as contrast agents for better visualization and sensing of the plaques. The review also points to an urgent need for nanotechnology as an efficient therapeutic strategy to increase the bioavailability of drugs in the central nervous system.


Assuntos
Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/patologia , Epigênese Genética , Humanos , Nanotecnologia , Placa Amiloide/patologia
9.
J Natl Black Nurses Assoc ; 30(1): 40-47, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31465684

RESUMO

The purpose of this article was to help healthcare practitioners understand the dynamics of Alzheimer's care giving and to introduce an evidence-based practice intervention to improve the caregiver's self-efficacy. Over 5 million people in the United States are afflicted with Alzheimer's disease and require a caregiver to assist with all areas of daily activity. Adult care giving is challenging for the caregiver, who is often a family member with little to no knowledge or skill in rendering care. African-American caregivers encounter an even greater challenge by overcoming cultural bias inherent in racial disparity. Evidence-based practice interventions are helpful in successfully rendering care while minimizing stress and burden. Healthcare providers must consider the caregiver, the dynamics of care giving, and cultural norms, in the plan of care to successfully care for the Alzheimer's patient along the trajectory of the disease.


Assuntos
Doença de Alzheimer/terapia , Cuidadores/psicologia , Planejamento de Assistência ao Paciente/organização & administração , Adulto , Afro-Americanos/psicologia , Características Culturais , Prática Clínica Baseada em Evidências , Humanos , Autoeficácia
10.
Nurs Clin North Am ; 54(3): 437-448, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31331629

RESUMO

Dementia is defined as loss of intellectual functions, including thinking, remembering, and reasoning. Cognitive deficits are severe enough to interfere with an individual's daily functioning. Frontotemporal dementia (FTD) is a result of degeneration of the frontal and/or temporal lobes of the brain. FTD is a leading cause of early-onset dementia in approximately 10% of dementia cases. FTD presents in the fourth and fifth decades as progressive changes in personality, affect, and behavior. The etiology of FTD is unknown; treatment focuses on behavioral and symptom management. Early recognition of FTD and knowledge of interventional strategies are needed to support families and caregivers.


Assuntos
Doença de Alzheimer/terapia , Terapia Comportamental/normas , Progressão da Doença , Demência Frontotemporal/fisiopatologia , Demência Frontotemporal/terapia , Guias de Prática Clínica como Assunto , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
11.
Nervenarzt ; 90(9): 891-897, 2019 Sep.
Artigo em Alemão | MEDLINE | ID: mdl-31332452

RESUMO

Alzheimer's disease is histopathologically characterized by aggregation of two proteins, namely amyloid-beta peptide and tau protein. Whereas former intervention trials focused particularly on the amyloid pathology, recent therapeutic approaches are directed against the tau pathology. This article summarizes recent progress in anti-tau therapies, especially therapies based on anti-tau immunization and antisense oligonucleotides (ASO).


Assuntos
Doença de Alzheimer , Proteínas tau , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Humanos , Imunoterapia , Oligonucleotídeos Antissenso/uso terapêutico , Proteínas tau/antagonistas & inibidores , Proteínas tau/metabolismo
13.
J Manag Care Spec Pharm ; 25(7): 800-809, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31232206

RESUMO

BACKGROUND: Headlines in popular media suggest that Alzheimer disease will bankrupt the Medicare program. Indeed, Alzheimer disease affects more than 5 million older Medicare beneficiaries. OBJECTIVE: To compare total Medicare-covered (allowed) costs of patients with Alzheimer disease with the risk adjusted costs of beneficiaries without dementia over their last years of life, using claims data. METHODS: Using the Medicare 5 Percent Limited Data Set claim files from 2006-2015, we conducted a cost impact analysis of costs for up to 8 years before the year of death. Risk adjustment was performed at a beneficiary level using Medicare's 2015 Hierarchical Condition Categories. Beneficiaries were classified into dementia categories based on their diagnoses during the last 3 years of life. Costs were trend adjusted to 2015. RESULTS: This study found that 40% of deceased beneficiaries have Alzheimer disease or unspecified dementia diagnoses in their claims history. In their last 9 years of life, Alzheimer disease added about 11% to the average $17,000 per year Medicare cost for same-risk beneficiaries without dementia. CONCLUSIONS: Like many diseases, Alzheimer disease and dementia are associated with aging, but unlike other diseases, families and Medicaid, rather than Medicare, bear most of the substantial cost burden. As research continues into Alzheimer treatments, it is not too early to consider how to better integrate Medicare and Medicaid to fund and improve patient outcomes, which will likely involve better diagnosis, treatment, and care coordination. DISCLOSURES: Funding for this project was provided by the Alliance for Aging Research, which received funding from Biogen, Eli Lilly, and Janssen Pharmaceuticals. Peschin and Jenkins are employed by the Alliance for Aging Research. Scott was employed by the Alliance for Aging Research at the time of this study and also reports consulting fees from Piramal Imaging, General Electric, and Allergan, outside of this study. Scott is chair of the Board of Directors for the Alliance for Aging Research, which is a volunteer position, and is also president of Applied Policy, a health policy and reimbursement consultancy. Pyenson and Steffens are employed by Milliman, which was contracted to work on this study. Goss Sawhney and Rotter were employed by Milliman at the time this work was performed. Milliman is a consultant to thousands of organizations in the health care industry.


Assuntos
Doença de Alzheimer/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Política de Saúde/economia , Medicare/economia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Efeitos Psicossociais da Doença , Demência/diagnóstico , Demência/economia , Demência/terapia , Feminino , Humanos , Masculino , Estados Unidos
14.
Adv Gerontol ; 32(1-2): 112-120, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31228376

RESUMO

The article deals with the important issue of diagnosis and treatment of Alzheimer's disease in the elderly and senile age. Despite the fact that this disease is considered, of course, age-associated pathology, which is the main cause of senile dementia, its diagnosis in Russia is exhibited rather rarely compared with dementia, for example, of vascular origin. This is due, in the author's opinion, not only with the difficulties of in-vivo diagnosis of Alzheimer's disease, but, first of all, with the characteristic of the elderly and senile multiplicity of pathological processes. A significant part of these pathologic processes, as well as Alzheimer's disease, can cause increasing cognitive disorders. Under this condition, dementia is already considered as a multi-factorial disease even in cases where Alzheimer's disease is the leading factor. This position, in turn, requires the expansion of the diagnostic search even in cases of full confidence in the diagnosis of Alzheimer's disease in the elderly and senile age to determine the possible role of other pathological processes in the formation and development of dementia. Ultimately, with limited opportunities for treatment of Alzheimer's disease, this will help in the selection of treatment methods aimed at reducing the role of other etiological and pathogenic moments in the development of dementia of mixed Genesis in the elderly and senile.


Assuntos
Doença de Alzheimer , Transtornos Cognitivos , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/terapia , Transtornos Cognitivos/etiologia , Humanos , Federação Russa
15.
Life Sci ; 231: 116564, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202840

RESUMO

Alzheimer's disease (AD) as a dementia and neurodegenerative disease, is mostly prevalent among people more than 65 years. AD is mostly manifested in the form of degraded mental function, such as losing memory and impaired cognitive function. Due to inefficiency of traditional pharmacological therapeutic approaches with no long-term cure, cell therapy can be considered as a capable approach in AD management. Therapies based on mesenchymal stem cells (MSCs) have provided hopeful results in experimental models regarding several disorders. MSCs enhance the levels of functional recoveries in pathologic experimental models of central nervous system (CNS) and are being investigated in clinical trials in neurological disorders. However, there is limited knowledge on the protective capabilities of MSCs in AD management. Almost, several experiments have suggested positive effects of MSCs and helped to better understand of AD-related dementia mechanism. MSCs have the potential to be used in AD treatment through amyloid-ß peptide (AB), Tau protein and cholinergic system. This review aimed to clarify the promising perspective of MSCs in the context of AD.


Assuntos
Doença de Alzheimer/terapia , Transplante de Células-Tronco Mesenquimais/métodos , Animais , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/fisiologia , Ensaios Clínicos Controlados Aleatórios como Assunto
16.
Zhongguo Zhen Jiu ; 39(5): 551-5, 2019 May 12.
Artigo em Chinês | MEDLINE | ID: mdl-31099230

RESUMO

OBJECTIVE: To explore the acupoint selection rules of acupuncture for Alzheimer's disease (AD) in modern clinical practice by complex network technology. METHODS: The relevant articles of clinical trials were retrieved from CNKI published before December 2017. Using Microsoft Excel 2010, the database was established. Using Gephi 0.8.2 software, the complex network mode was built and its topological structure was analyzed. RESULTS: Finally, 81 articles were eligible and 114 acupoint prescriptions were extracted. The constructed complex network of acupoint prescriptions for AD was characteristics as small world effect and scale-free property, the crucial acupoints included Baihui (GV 20), Sishencong (EX-HN 1), Fengchi (GB 20), Yintang (GV 29), Shenmen (HT 7), Shenting (GV 24), Zusanli (ST 36), Fenglong (ST 40) and Taichong (LR 3). In acupoint combination, Baihui (GV 20), Neiguan (PC 6), Shenmen (HT 7) and Sanyinjiao (SP 6) were the most common, and the combination of the distal and nearby points was predominant. Using k-core for acupoint optimization, 29 core acupoints were screened and they were mostly located on the governor vessel and the head and neck, with the highest use frequency. 82.76% of acupoints were specific acupoints and the influential points were dominant. Using community structure partition, these acupoints were classified into two groups, i.e. deficiency syndrome and excess syndrome. CONCLUSION: The selection of local acupoints is the first choice in acupuncture treatment for AD. The combination of distal and nearby points is the most common and the special points are the core. In clinical practice, the great consideration is provided on mind regulation, integration of disease and symptoms, the mutual treatment of the primary and the secondary as well as the deficiency and the excess.


Assuntos
Pontos de Acupuntura , Doença de Alzheimer , Publicações , Doença de Alzheimer/terapia , Bases de Dados Factuais , Humanos
17.
Cell Mol Life Sci ; 76(19): 3681-3694, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31093687

RESUMO

The prominent pathological consequences of Alzheimer's disease (AD) are the misfolding and mis-sorting of two cellular proteins, amyloid-ß and microtubule-associated protein Tau. The accumulation of toxic phosphorylated Tau inside the neurons induces the increased processing of amyloid-ß-associated signaling cascade and vice versa. Neuroinflammation-driven synaptic depletion and cognitive decline are substantiated by the cross talk of activated microglia and astroglia, leading to neuron degeneration. Microglia are the brain-resident immune effectors that prove their diverse functions in maintaining CNS homeostasis via collaboration with astrocytes and T lymphocytes. Age-related senescence and chronic inflammation activate microglia with increased pro-inflammatory markers, oxidative damage and phagocytosis. But the improper processing of misfolded protein via lysosomal pathway destines the spreading of 'seed' constituents to the nearby healthy neurons. Primed microglia process and present self-antigen such as amyloid-ß and modified Tau to the infiltrated T lymphocytes through MHC I/II molecules. After an effective conversation with CD4+ T cells, microglial phenotype can be altered from pro-active M1 to neuro-protective M2 type, which corresponds to the tissue remodeling and homeostasis. In this review, we are focusing on the change in functionality of microglia from innate to adaptive immune response in the context of neuroprotection, which may help in the search of novel immune therapy in AD.


Assuntos
Doença de Alzheimer/imunologia , Apresentação do Antígeno , Microglia/imunologia , Imunidade Adaptativa , Doença de Alzheimer/terapia , Encéfalo/imunologia , Humanos , Imunoterapia , Neuroimunomodulação , Dobramento de Proteína , Linfócitos T/imunologia
18.
Expert Opin Investig Drugs ; 28(6): 545-554, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31094578

RESUMO

INTRODUCTION: Alzheimer's dementia (AD) is the most common form of dementia in the World. Pathologically, it is characterized by extracellular ß-amyloid plaques and intraneuronal neurofibrillary tangles (NFTs). The latter is composed of irregular, pathological forms of the tau protein. Currently, FDA-approved symptomatic treatments are limited to the targeting of cholinergic deficits and glutamatergic dysfunctions. However, as understanding of ß-amyloid plaques and NFTs expands, these dysfunctional proteins represent potential therapeutic interventions. The present review article evaluates active and passive immunotherapies in clinical development for AD to date and their potential to significantly improve the treatment of AD going forward. AREAS COVERED: All clinical trials that have targeted ß-amyloid to date have produced somewhat disappointing results, leading to a shift in intervention focus to targeting tau protein. A key component in understanding the value of targeting tau in therapeutic paradigms has come from the conceptualization of prion-like pathological spread of tau isoforms from neuron to neuron, and referred to as 'tauons'. Immunotherapies currently under investigation include approaches aiming at preventing pathological tau aggregation, stabilizing microtubules, and blocking of tauons. EXPERT OPINION: A multi-targeted approach that would use biologics targeting tau offers great promise to the development of effective AD therapeutic interventions.


Assuntos
Doença de Alzheimer/terapia , Imunoterapia/métodos , Proteínas tau/imunologia , Doença de Alzheimer/imunologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/metabolismo , Animais , Produtos Biológicos/farmacologia , Humanos , Terapia de Alvo Molecular , Emaranhados Neurofibrilares/metabolismo , Proteínas tau/metabolismo
19.
Life Sci ; 231: 116483, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31102743

RESUMO

Alzheimer's disease (AD) remains one of the greatest global concerns. Current treatment of AD - the acetylcholinesterase inhibitors - provides temporary improvement of cognitive functions, but does not affect the core of the underlying pathological process. There is still the need for alternative approaches, preferably ones based on the upstream events in the AD pathogenesis. The nature of AD pathogenesis remains complicated and not entirely explained. It is assumed to comprise of many interrelated events which can sequentially lead to further pathologies - as a kind of vicious cycle. The solution in this case could be to interact with these processes on multiple levels at the same time. The proposed approach hopes to achieve the state of equilibrium between two pathological pathways via reducing their dynamics on appropriate levels. The first step is to inhibit Tumor Necrosis Factor signaling related to inflammatory response. The second is to take advantage of the influence of insulin signaling on amyloid-ß processing to restore its proper clearance. Employing two only partially-beneficial approaches into a novel approach aims at breaking the "vicious cycle" and eliciting synergistic effect via working on different levels simultaneously. The effect of such therapy could allow physicians to completely inhibit neural damage. The proposed strategy may prove easily introducible as an efficacious clinical approach employing novel anti-TNF agents in combination with anti-diabetic agents. Data is needed on its influence on cognitive functions, any occurrence of adverse effects, and the development of models of optimal doses and their temporal location.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Diabetes Mellitus/terapia , Inflamação/terapia , Anti-Inflamatórios/uso terapêutico , Cognição , Demência/tratamento farmacológico , Demência/fisiopatologia , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Sinergismo Farmacológico , Humanos , Hipoglicemiantes/uso terapêutico , Inflamação/metabolismo , Insulina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
20.
Adv Exp Med Biol ; 1128: 227-248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062332

RESUMO

Recently, Alzheimer's disease (AD) is understood as "diabetes of the brain" or "type 3 diabetes." Recent clinical trials of anti-amyloid ß-protein (Aß) therapies have not proved to be successful. Thus, glucose-insulin metabolism in the brain is thought to be an alternative therapeutic target. Various types of antidiabetic drugs such as insulin, thiazolidinediones, dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, biguanides, and others have been reported to be effective on cognitive impairment in animal models and patients with DM or AD. Here, recent reports are reviewed. While we identified apomorphine (APO) as a novel drug that promoted intracellular Aß degradation and improved memory function in an AD mouse model, more recently, we have revealed that APO treatment improves neuronal insulin resistance and activates insulin-degrading enzyme (IDE), a major Aß-degrading enzyme. In this context, recovery of impaired insulin signaling in AD neurons may be a promising therapeutic strategy for AD dementia.


Assuntos
Doença de Alzheimer/complicações , Doença de Alzheimer/terapia , Apomorfina/uso terapêutico , Diabetes Mellitus , Peptídeos beta-Amiloides , Animais , Humanos , Insulina , Insulisina , Camundongos
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