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1.
Adv Exp Med Biol ; 1173: 67-104, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456206

RESUMO

Alzheimer's disease (AD) is a multifactorial neurodegenerative condition associated with pathological accumulation of amyloid plaques and with the appearance of deposit of neurofibrillary tangles. Increasing evidence suggests that disorders of metal ion metabolism in the brain are one of the risk factors for the pathogenesis of AD. Iron, one of the endogenous metal ions, involves in many important physiological activities in the brain. Iron metabolism mainly depends on iron regulatory proteins including ferritin, transferrin and transferrin receptor, hepcidin, ferroportin, lactoferrin. Abnormal iron metabolism generates hydroxyl radicals through the Fenton reaction, triggers oxidative stress reactions, damages cell lipids, protein and DNA structure and function, leads to cell death, and ultimately influences the process of ß-amyloid (Aß) misfolding and plaque aggregation. Although the results are different, in general, iron has deposition in different brain regions of AD patients, which may impair normal cognitive function and behavior. Therefore, neuroimaging changes have so far been largely attributed to focal iron deposition accompanying the plaques at preclinical stages of AD, and iron-targeted therapeutic strategies have become a new direction. Iron chelators have received a great deal of attention and have obtained good results in scientific experiments and some clinical trials. Future research will also focus on iron as an opportunity to study the mechanism of the occurrence and development of AD from the iron steady state to more fully clarify the etiology and prevention strategies.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/metabolismo , Ferro/metabolismo , Peptídeos beta-Amiloides , Encéfalo/fisiopatologia , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia
2.
Chem Commun (Camb) ; 55(67): 9955-9958, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31364619

RESUMO

A silver nanocluster-based ratiometric fluorescent nanosensor was developed for the determination of ATP in the cerebrospinal fluid of a mouse brain. Using this useful tool with good stability and high selectivity as well as a wide linear detection range, it was found that the ATP concentration in a mouse brain with Alzheimer's disease was 2300-fold higher than that in a normal one.


Assuntos
Trifosfato de Adenosina/líquido cefalorraquidiano , Química Encefálica , DNA/química , Corantes Fluorescentes/química , Nanopartículas Metálicas/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/citologia , Encéfalo/patologia , Córtex Cerebral/química , Hipocampo/química , Camundongos , Conformação de Ácido Nucleico , Prata/química , Espectrometria de Fluorescência/métodos
3.
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
4.
J Assoc Physicians India ; 67(4): 14-17, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31299831

RESUMO

Background: White matter hyperintensities (WMH) on MRI brain in the periventricular and deep white matter regions are commonly seen in older persons with normal cognition and in patients with AD. Aims: To compare presence and severity of WMHs in patients with AD with that in a cognitively normal control group, and to evaluate effect of presence of Hypertension and Diabetes on WMHs in both groups. Material and Methods: Thirty four patients with AD were serially recruited from Neurology and Psychiatry OPDs. An age and gender matched cohort of 24 persons with MMSE over 27/30 from the community acted as controls. Vascular risk factors, MMSE and MRI brain were assessed in all. Fezeka's and Pasquier grading of WMH and atrophy were done. Periventricular WMHs (PVWMH) and Deep WMH (DWMH) were assessed separately. Results and Conclusions: Overall, Periventricular WMHs of grade 2 and over were seen in 19/34 patients, and in 7/24 controls (P value 0.044). Significantly higher grades of PVWMHs were seen in hypertensives as compared to nonhypertensives in the case group, and in women compared to men. In the control group, hypertension had no effect on severity of PVWMHs. Among both Diabetics and non-diabetics, no difference in PVWMHs was found between the case and control groups. DWMHs were, conversely, seen only in the control group. Overall, over a quarter of cognitively normal older persons had WM hyperintensities of grade 2 and over on MRI brain; 55% of AD patients had PVWMH of Gd 2 or over, and no DWMHs.


Assuntos
Doença de Alzheimer/patologia , Diabetes Mellitus/patologia , Hipertensão/patologia , Substância Branca , Idoso , Idoso de 80 Anos ou mais , Grupos Controle , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
5.
Nat Commun ; 10(1): 3090, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300647

RESUMO

The role of brain somatic mutations in Alzheimer's disease (AD) is not well understood. Here, we perform deep whole-exome sequencing (average read depth 584×) in 111 postmortem hippocampal formation and matched blood samples from 52 patients with AD and 11 individuals not affected by AD. The number of somatic single nucleotide variations (SNVs) in AD brain specimens increases significantly with aging, and the rate of mutation accumulation in the brain is 4.8-fold slower than that in AD blood. The putatively pathogenic brain somatic mutations identified in 26.9% (14 of 52) of AD individuals are enriched in PI3K-AKT, MAPK, and AMPK pathway genes known to contribute to hyperphosphorylation of tau. We show that a pathogenic brain somatic mutation in PIN1 leads to a loss-of-function mutation. In vitro mimicking of haploinsufficiency of PIN1 aberrantly increases tau phosphorylation and aggregation. This study provides new insights into the genetic architecture underlying the pathogenesis of AD.


Assuntos
Doença de Alzheimer/genética , Peptidilprolil Isomerase de Interação com NIMA/genética , Agregação Patológica de Proteínas/genética , Proteínas tau/metabolismo , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Doença de Alzheimer/patologia , Animais , Linhagem Celular Tumoral , Feminino , Técnicas de Silenciamento de Genes , Haploinsuficiência , Hipocampo/citologia , Hipocampo/patologia , Humanos , Mutação com Perda de Função , Masculino , Camundongos , Pessoa de Meia-Idade , Taxa de Mutação , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Neurônios , Fosforilação/genética , Polimorfismo de Nucleotídeo Único , Agregação Patológica de Proteínas/patologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Sequenciamento Completo do Exoma
6.
Nat Neurosci ; 22(7): 1099-1109, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31235907

RESUMO

Parkinson's disease, the most common age-related movement disorder, is a progressive neurodegenerative disease with unclear etiology. Key neuropathological hallmarks are Lewy bodies and Lewy neurites: neuronal inclusions immunopositive for the protein α-synuclein. In-depth ultrastructural analysis of Lewy pathology is crucial to understanding pathogenesis of this disease. Using correlative light and electron microscopy and tomography on postmortem human brain tissue from Parkinson's disease brain donors, we identified α-synuclein immunopositive Lewy pathology and show a crowded environment of membranes therein, including vesicular structures and dysmorphic organelles. Filaments interspersed between the membranes and organelles were identifiable in many but not all α-synuclein inclusions. Crowding of organellar components was confirmed by stimulated emission depletion (STED)-based super-resolution microscopy, and high lipid content within α-synuclein immunopositive inclusions was corroborated by confocal imaging, Fourier-transform coherent anti-Stokes Raman scattering infrared imaging and lipidomics. Applying such correlative high-resolution imaging and biophysical approaches, we discovered an aggregated protein-lipid compartmentalization not previously described in the Parkinsons' disease brain.


Assuntos
Membranas Intracelulares/ultraestrutura , Corpos de Lewy/ultraestrutura , Doença por Corpos de Lewy/patologia , Lipídeos de Membrana/análise , Organelas/ultraestrutura , Doença de Parkinson/patologia , alfa-Sinucleína/análise , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Hipocampo/química , Hipocampo/ultraestrutura , Humanos , Imagem Tridimensional , Corpos de Lewy/química , Doença por Corpos de Lewy/metabolismo , Mesencéfalo/química , Mesencéfalo/ultraestrutura , Microscopia Confocal , Microscopia Eletrônica/métodos , Microscopia de Fluorescência , Doença de Parkinson/metabolismo , Substância Negra/química , Substância Negra/ultraestrutura , Sequenciamento Completo do Exoma
7.
Cell Mol Life Sci ; 76(16): 3167-3191, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31197405

RESUMO

As life expectancy increases worldwide, age-related neurodegenerative diseases will increase in parallel. The lack of effective treatment strategies may soon lead to an unprecedented health, social and economic crisis. Any attempt to halt the progression of these diseases requires a thorough knowledge of the pathophysiological mechanisms involved to facilitate the identification of new targets and the application of innovative therapeutic strategies. The metzincin superfamily of metalloproteinases includes matrix metalloproteinases (MMP), a disintegrin and metalloproteinase (ADAM) and ADAM with thrombospondin motifs (ADAMTS). These multigenic and multifunctional proteinase families regulate the functions of an increasing number of signalling and scaffolding molecules involved in neuroinflammation, blood-brain barrier disruption, protein misfolding, synaptic dysfunction or neuronal death. Metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are therefore, at the crossroads of molecular and cellular mechanisms that support neurodegenerative processes, and emerge as potential new therapeutic targets. We provide an overview of current knowledge on the role and regulation of metalloproteinases and TIMPs in four major neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease.


Assuntos
Doença de Alzheimer/patologia , Metaloproteinases da Matriz/metabolismo , Doenças Neurodegenerativas/patologia , Inibidores Teciduais de Metaloproteinases/metabolismo , Proteínas ADAM/metabolismo , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Humanos , Doença de Huntington/metabolismo , Doença de Huntington/patologia , Doenças Neurodegenerativas/metabolismo , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia
8.
Cell Mol Life Sci ; 76(16): 3193-3206, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201463

RESUMO

Alzheimer's Disease (AD) is the sixth-leading cause of death in industrialized countries. Neurotoxic amyloid-ß (Aß) plaques are one of the pathological hallmarks in AD patient brains. Aß accumulates in the brain upon sequential, proteolytic processing of the amyloid precursor protein (APP) by ß- and γ-secretases. However, so far disease-modifying drugs targeting ß- and γ-secretase pathways seeking a decrease in the production of toxic Aß peptides have failed in clinics. It has been demonstrated that the metalloproteinase meprin ß acts as an alternative ß-secretase, capable of generating truncated Aß2-x peptides that have been described to be increased in AD patients. This indicates an important ß-site cleaving enzyme 1 (BACE-1)-independent contribution of the metalloprotease meprin ß within the amyloidogenic pathway and may lead to novel drug targeting avenues. However, meprin ß itself is embedded in a complex regulatory network. Remarkably, the anti-amyloidogenic α-secretase a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) is a direct competitor for APP at the cell surface, but also a sheddase of inactive pro-meprin ß. Overall, we highlight the current cellular, molecular and structural understanding of meprin ß as alternative ß-secretase within the complex protease web, regulating APP processing in health and disease.


Assuntos
Proteína ADAM10/metabolismo , Metaloendopeptidases/metabolismo , Proteína ADAM10/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Metaloendopeptidases/química , Presenilina-1/metabolismo , Proteólise , Serina Endopeptidases/metabolismo
9.
Chem Biol Interact ; 309: 108707, 2019 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-31194956

RESUMO

Alzheimer's disease (AD) is a slow but progressive neurodegenerative disease. One of the pathological hallmarks of AD is the progressive accumulation of ß-amyloid (Aß) in the form of senile plaques, and Aß insult to neuronal cells has been identified as one of the major causes of AD onset. In the present study, we investigated the anti-AD potential of four flavonoids, naringenin, didymin, prunin, and poncirin, by evaluating their ability to inhibit acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ß-site amyloid precursor protein cleaving enzyme 1 (BACE1). All four flavonoids displayed promising inhibitory activity against AChE, BChE, and BACE1. Structure-activity relationships suggested that glycosylation of naringenin at sugar moieties, and at different positions of the glycosidic linkage, might be closely associated with anti-AD potential. Kinetic and docking studies showed the lowest binding energy and highest affinity for the mixed, competitive, and non-competitive type inhibitors didymin, prunin, and poncirin. Hydrophobic interactions and the number of hydrogen bonds determined the strength of the protein-inhibitor interaction. We also examined the neuroprotective mechanisms by which flavonoids act against Aß25-35-induced toxicity in PC12 cells. Exposure of PC12 cells to 10 µM Aß25-35 for 24 h resulted in a significant decrease in cell viability. In addition, pretreatment of PC12 cells with different concentrations of flavonoids for 1 h significantly reversed the effects of Aß. Furthermore, treatment with the most active flavonoid, didymin, significantly reduced BACE1, APPsß, and C99 expression levels in a dose-dependent manner, without affecting amyloid precursor protein (APP) levels in the amyloidogenic pathway. Together, our results indicate that flavonoids, and in particular didymin, exhibit inhibitory activity in vitro, and may be useful in the development of therapeutic modalities for the treatment of AD.


Assuntos
Acetilcolinesterase/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Butirilcolinesterase/metabolismo , Flavanonas/química , Glicosídeos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Acetilcolinesterase/química , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/farmacologia , Animais , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Sítios de Ligação , Butirilcolinesterase/química , Domínio Catalítico , Sobrevivência Celular/efeitos dos fármacos , Glicosídeos/química , Cinética , Simulação de Acoplamento Molecular , Células PC12 , Fragmentos de Peptídeos/farmacologia , Substâncias Protetoras/química , Substâncias Protetoras/farmacologia , Ratos , Relação Estrutura-Atividade
10.
Brain Nerve ; 71(6): 589-596, 2019 Jun.
Artigo em Japonês | MEDLINE | ID: mdl-31171756

RESUMO

Complements are deposited in senile plaques, neurofibrillary tangles, and blood vessels. Microglia is activated around these structures and induce chronic inflammation through a cross talk between microglia and astroglia. Complements activated by amyloidß (Aß) bind to complement receptor (CR3) and help phagocytosis of the aggregated Aß via opsonization of the aggregated Aß. Inflammation in capillary cerebral amyloid angiopathy (CAA) may suppress Aßclearance and trigger a vicious cycle aggravating CAA.


Assuntos
Doença de Alzheimer/patologia , Angiopatia Amiloide Cerebral/patologia , Proteínas do Sistema Complemento , Humanos , Emaranhados Neurofibrilares , Placa Amiloide
11.
Front Neurol Neurosci ; 44: 118-126, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31220848

RESUMO

The term dementia derives from the Latin root demens, which means being out of one's mind. Although the term "dementia" has been used since the 13th century, its mention in the medical community was reported in the 18th century. Even though the Greeks postulated a cerebral origin, the concept was not restricted to senile dementia and included all sorts of psychiatric and neurological conditions leading to psychosocial consequences. In the 19th century, individuals with dementia were recognized as patients, deserving medical care from specialists called alienists, and senile dementia became a medical disease. Subsequently, progresses in neuropathology allowed its fragmentation into different neuropathological conditions. Senile dementia was considered as a distinct entity from Alzheimer's seminal case published in 1906, and was first attributed to a vascular origin. However, from the late 1960s and for 20 subsequent years, Alzheimer's disease became the prototypical senile dementia. Only recently, the term dementia was abandoned for major neurocognitive disorder and the heterogeneity of the syndrome acknowledged again at the phenotypical and molecular levels. We hope a better understanding of this fascinating history will improve scientific research and impose humility towards the complex underpinnings of age-related cognitive decline.


Assuntos
Doença de Alzheimer/história , Encéfalo/patologia , Demência/história , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/patologia , Encefalopatias/diagnóstico , Encefalopatias/história , Demência/diagnóstico , Demência/etiologia , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Síndrome
12.
Yonsei Med J ; 60(7): 640-650, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31250578

RESUMO

PURPOSE: Alzheimer's disease (AD) is the most common neurodegenerative disease, with a rising prevalence worldwide. Long noncoding RNAs (lncRNAs) have been found to play important roles in the development and treatment of AD. However, the exact role of lncRNA nuclear enriched abundant transcript 1 (NEAT1) in neuronal damage in AD is largely unknown. MATERIALS AND METHODS: The AD model was established in SH-SY5Y and SK-N-SH cells via treatment with amyloid ß1-42 (Aß). The expression of NEAT1 and microRNA-107 (miR-107) was measured by quantitative real-time polymerase chain reaction. Cell viability and apoptosis were detected by MTT assay, immunocytochemistry, and flow cytometry. The expression of phosphorylated tau protein (p-Tau) was measured by Western blot. The interaction between NEAT1 and miR-107 was explored by bioinformatics analysis, luciferase activity, and RNA immunoprecipitation assays. RESULTS: NEAT1 expression was enhanced in Aß-treated SH-SY5Y and SK-N-SH cells, and its knockdown attenuated Aß-induced inhibition of viability and promotion of apoptosis and p-Tau levels. NEAT1 was indicated as a decoy of miR-107. miR-107 abundance was reduced in Aß-treated cells, and its overexpression reversed Aß-induced injury. Moreover, interference of miR-107 abated silencing of NEAT1-mediated inhibition of neuronal damage in Aß-treated SH-SY5Y and SK-N-SH cells. CONCLUSION: LncRNA NEAT1 aggravated Aß-induced neuronal damage by sponging miR-107, indicating a novel avenue for treatment of AD.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/toxicidade , MicroRNAs/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fragmentos de Peptídeos/toxicidade , RNA Longo não Codificante/genética , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Humanos , Neurônios/patologia
13.
Nat Commun ; 10(1): 2394, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160584

RESUMO

To understand the molecular processes that link Aß amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer's disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Doença de Alzheimer/metabolismo , Hipocampo/metabolismo , Agregação Patológica de Proteínas/metabolismo , Células Piramidais/metabolismo , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Animais , Atrofia , Caspase 3/metabolismo , Morte Celular , Cromatografia Líquida , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Neurônios/metabolismo , Neurônios/patologia , Agregação Patológica de Proteínas/patologia , Células Piramidais/patologia , Tauopatias , Proteínas tau/metabolismo
14.
Mol Med Rep ; 19(6): 4897-4905, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31059028

RESUMO

Amyloid ß (Aß) has been reported to have an important role in the cognitive deficits of Alzheimer's disease (AD), as oligomeric Aß promotes synaptic dysfunction and triggers neuronal death. Recent evidence has associated an endocytosis protein, endophilin 1, with AD, as endophilin 1 levels have been reported to be markedly increased in the AD brain. The increase in endophilin 1 levels in neurons is associated with an increase in the activation of the stress kinase JNK, with subsequent neuronal death. In the present study, whole­cell patch­clamp recording demonstrated that oligomeric Aß caused synaptic dysfunction and western blotting revealed that endophilin 1 was highly expressed prior to neuronal death of cultured hippocampal neurons. Furthermore, RNA interference and electrophysiological recording techniques in cultured hippocampal neurons demonstrated that knockdown of endophilin 1 prevented synaptic dysfunction induced by Aß. Thus, a potential role for endophilin 1 in Aß­induced postsynaptic dysfunction has been identified, indicating a possible direction for the prevention of postsynaptic dysfunction in cognitive impairment and suggesting that endophilin may be a potential target for the clinical treatment of AD.


Assuntos
Aciltransferases/metabolismo , Peptídeos beta-Amiloides/farmacologia , Neurônios/efeitos dos fármacos , Fragmentos de Peptídeos/farmacologia , Sinapses/efeitos dos fármacos , Aciltransferases/antagonistas & inibidores , Aciltransferases/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Polímeros/química , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Sinapses/fisiologia
15.
Maturitas ; 124: 8-14, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097184

RESUMO

Increasing evidence suggests a bidirectional relationship exists between levels of health literacy (HL) and cognitive impairment in later life. However, it is unclear whether low levels of HL can lead to a higher risk of dementia. This systematic review explored prospective cohort studies to find out whether HL is a risk factor for incident dementia in older adults. A search was conducted in Medline, PsycINFO, Embase, PubMed and Scopus and 5450 documents were initially retrieved. The grey literature and references of the selected papers were also consulted. Papers were selected and assessed by three researchers independently. Findings were reported in line with the PRISMA guidelines and quality appraisal was conducted using the STROBE checklist. Four studies were included for quality appraisal, data extraction and synthesis, all of which were conducted in the United States between 2014 and 2018. Adjusted analyses showed that in all studies people with low levels of HL had a significantly higher risk of incident dementia over time than people with adequate levels of HL. Low HL or total literacy (financial plus HL) was also a risk factor for mild cognitive impairment in two studies, irrespective of an Alzheimer's disease genotype. There was a statistically significant positive association between total literacy scores and the post-mortem amount of plaques and tangles suggestive of Alzheimer's disease. Our findings suggest that low levels of HL might lead to higher future dementia risk. However, as only a few longitudinal studies have been conducted in this area, further research is needed to establish the role of HL as a key risk factor for dementia. Researchers should use standardized HL-specific measurement tools so that future studies in this area are robust and comparable. Primary health care professionals might wish consider individual's HL when planning and implementing dementia risk reduction in order to improve its long-term effectiveness.


Assuntos
Demência/epidemiologia , Alfabetização em Saúde , Idoso , Doença de Alzheimer/epidemiologia , Doença de Alzheimer/patologia , Humanos , Incidência , Estudos Prospectivos , Fatores de Risco
16.
Med Sci Monit ; 25: 3329-3335, 2019 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-31056537

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of ß-amyloid peptide 1-42 and phosphorylation of tau protein in the brain. Thus far, the transfer mechanism of these cytotoxic proteins between nerve cells remains unclear. Recent studies have shown that nanoscale extracellular vesicles (exosomes) originating from cells may play important roles in this transfer process. In addition, several genetic materials and proteins are also involved in intercellular communication by the secretion of the exosomes. That proposes novel avenues for early diagnosis and biological treatment in AD, based on exosome detection and intervention. In this review, exosome-related pathways of cytotoxic protein intercellular transfer in AD, and the effect of membrane proteins on exosomes targeting cells are first introduced. The advances in exosome-related biomarker detection in AD are summarized. Finally, the advantages and challenges of reducing cytotoxic protein accumulation via exosomal intervention for AD treatment are discussed. It is envisaged that future research in exosomes may well provide new insights into the pathogenesis, diagnosis, and treatment of AD.


Assuntos
Doença de Alzheimer/patologia , Exossomos/patologia , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/terapia , Biomarcadores/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Exossomos/metabolismo , Humanos , Fosforilação , Proteínas tau/metabolismo
17.
Adv Exp Med Biol ; 1128: 45-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062325

RESUMO

The standard practice in neuropathology is to diagnose Alzheimer's disease (AD) based on the distribution and abundance of neurofibrillary tangles and Aß deposits. However, other significant abnormalities including neuroinflammation, gliosis, white matter degeneration, non-Aß microvascular disease, and insulin-related metabolic dysfunction require further study to understand how they could be targeted to more effectively remediate AD. This review addresses non-Aß and non-pTau AD-associated pathologies, highlighting their major features, roles in neurodegeneration, and etiopathic links to deficits in brain insulin and insulin-like growth factor signaling and cognitive impairment. The discussion delineates why AD with its most characteristic clinical and pathological phenotypic profiles should be regarded as a brain form of diabetes, i.e., type 3 diabetes, and entertains the hypothesis that type 3 diabetes is just one of the categories of insulin resistance diseases that can occur independently or overlap with one or more of the others, including type 2 diabetes, metabolic syndrome, and nonalcoholic fatty liver disease.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Diabetes Mellitus/patologia , Resistência à Insulina , Humanos , Insulina , Emaranhados Neurofibrilares/patologia
18.
Adv Exp Med Biol ; 1128: 85-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062326

RESUMO

Although the mechanisms by which Alzheimer's disease (AD) occurs remains unclear, it is widely accepted that both genetic and nongenetic components contribute to the pathogenesis of AD, especially the sporadic form of the disease. Nongenetic risk factors include diabetes and dyslipidemia, which are associated with impaired glucose and lipid metabolism, respectively. Apolipoprotein E (ApoE), one of the major lipid carriers in the brain, is the strongest genetic risk factor for late-onset AD. Several studies indicate that ApoE isoforms differentially affect not only lipid metabolism but also glucose metabolism or related pathways, suggesting that these risk factors contribute to the pathogenesis of AD through some common mechanisms. In this chapter, we discuss the roles of ApoE, lipids, and glucose in the pathogenesis of AD by considering their potential interactions.


Assuntos
Doença de Alzheimer/patologia , Apolipoproteínas E/genética , Glucose/metabolismo , Metabolismo dos Lipídeos , Doença de Alzheimer/genética , Encéfalo , Humanos
19.
Adv Exp Med Biol ; 1128: 133-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062328

RESUMO

Accumulating evidence suggests that diabetes mellitus (DM) is one of the strongest risk factors for developing Alzheimer's disease (AD). However, it remains unclear how DM accelerates AD pathology in the brain. Cynomolgus monkey (Macaca fascicularis) is one of the nonhuman primates used for biomedical research, and we can observe spontaneous formation of AD pathology, such as senile plaques (SPs) and neurofibrillary tangles (NFTs), with the advance of aging. Furthermore, obesity is occasionally observed and frequently leads to development of type II DM (T2DM) in laboratory-housed cynomolgus monkeys. These findings suggest that cynomolgus monkey is a useful species to study the relationship between T2DM and AD pathology. In T2DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices almost 5 years earlier than healthy control monkeys. Moreover, age-related endocytic pathology, such as intraneuronal accumulation of enlarged endosomes, was exacerbated in T2DM-affected monkey brains. Since accumulating evidences suggest that endocytic dysfunction is involved in Aß pathology, T2DM may aggravate age-related endocytic dysfunction, leading to the acceleration of Aß pathology.


Assuntos
Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/análise , Encéfalo/patologia , Diabetes Mellitus Tipo 2/complicações , Animais , Modelos Animais de Doenças , Macaca fascicularis , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia
20.
Adv Exp Med Biol ; 1128: 161-183, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31062330

RESUMO

Due to the exponential growth of aging population worldwide, neurodegenerative diseases became a major public health concern. Among them, Alzheimer's disease (AD) prevails as the most common in the elderly, rendering it a research priority. After several decades considering the brain as an insulin-insensitive organ, recent advances proved a central role for this hormone in learning and memory processes and showed that AD shares a high number of features with systemic conditions characterized by insulin resistance. Mitochondrial dysfunction has also been widely demonstrated to play a major role in AD development supporting the idea that this neurodegenerative disease is characterized by a pronounced metabolic dysregulation. This chapter is intended to discuss evidence demonstrating the key role of insulin signaling and mitochondrial anomalies in AD.


Assuntos
Doença de Alzheimer/patologia , Resistência à Insulina , Insulina/fisiologia , Mitocôndrias/patologia , Transdução de Sinais , Humanos
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