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1.
Gut ; 69(2): 283-294, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31471351

RESUMO

OBJECTIVE: Cerebral amyloidosis and severe tauopathy in the brain are key pathological features of Alzheimer's disease (AD). Despite a strong influence of the intestinal microbiota on AD, the causal relationship between the gut microbiota and AD pathophysiology is still elusive. DESIGN: Using a recently developed AD-like pathology with amyloid and neurofibrillary tangles (ADLPAPT) transgenic mouse model of AD, which shows amyloid plaques, neurofibrillary tangles and reactive gliosis in their brains along with memory deficits, we examined the impact of the gut microbiota on AD pathogenesis. RESULTS: Composition of the gut microbiota in ADLPAPT mice differed from that of healthy wild-type (WT) mice. Besides, ADLPAPT mice showed a loss of epithelial barrier integrity and chronic intestinal and systemic inflammation. Both frequent transfer and transplantation of the faecal microbiota from WT mice into ADLPAPT mice ameliorated the formation of amyloid ß plaques and neurofibrillary tangles, glial reactivity and cognitive impairment. Additionally, the faecal microbiota transfer reversed abnormalities in the colonic expression of genes related to intestinal macrophage activity and the circulating blood inflammatory monocytes in the ADLPAPT recipient mice. CONCLUSION: These results indicate that microbiota-mediated intestinal and systemic immune aberrations contribute to the pathogenesis of AD in ADLPAPT mice, providing new insights into the relationship between the gut (colonic gene expression, gut permeability), blood (blood immune cell population) and brain (pathology) axis and AD (memory deficits). Thus, restoring gut microbial homeostasis may have beneficial effects on AD treatment.


Assuntos
Doença de Alzheimer/microbiologia , Doença de Alzheimer/terapia , Transplante de Microbiota Fecal , Microbioma Gastrointestinal/fisiologia , Doença de Alzheimer/metabolismo , Animais , Comportamento Animal , Doença Crônica , Modelos Animais de Doenças , Humanos , Inflamação/microbiologia , Intestinos/microbiologia , Memória de Curto Prazo , Camundongos Transgênicos , Permeabilidade , Placa Amiloide/microbiologia , Placa Amiloide/patologia , Aprendizagem Espacial , Proteínas tau/análise
2.
Nat Rev Neurol ; 16(1): 30-42, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827267

RESUMO

The shared role of amyloid-ß (Aß) deposition in cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD) is arguably the clearest instance of crosstalk between neurodegenerative and cerebrovascular processes. The pathogenic pathways of CAA and AD intersect at the levels of Aß generation, its circulation within the interstitial fluid and perivascular drainage pathways and its brain clearance, but diverge in their mechanisms of brain injury and disease presentation. Here, we review the evidence for and the pathogenic implications of interactions between CAA and AD. Both pathologies seem to be driven by impaired Aß clearance, creating conditions for a self-reinforcing cycle of increased vascular Aß, reduced perivascular clearance and further CAA and AD progression. Despite the close relationship between vascular and plaque Aß deposition, several factors favour one or the other, such as the carboxy-terminal site of the peptide and specific co-deposited proteins. Amyloid-related imaging abnormalities that have been seen in trials of anti-Aß immunotherapy are another probable intersection between CAA and AD, representing overload of perivascular clearance pathways and the effects of removing Aß from CAA-positive vessels. The intersections between CAA and AD point to a crucial role for improving vascular function in the treatment of both diseases and indicate the next steps necessary for identifying therapies.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Angiopatia Amiloide Cerebral/metabolismo , Transdução de Sinais/fisiologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/genética , Encéfalo/patologia , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/patologia , Humanos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia
3.
EMBO J ; 38(23): e102345, 2019 12 02.
Artigo em Inglês | MEDLINE | ID: mdl-31701556

RESUMO

In Alzheimer's disease, BACE1 protease initiates the amyloidogenic processing of amyloid precursor protein (APP) that eventually results in synthesis of ß-amyloid (Aß) peptide. Aß deposition in turn causes accumulation of BACE1 in plaque-associated dystrophic neurites, thereby potentiating progressive Aß deposition once initiated. Since systemic pharmacological BACE inhibition causes adverse effects in humans, it is important to identify strategies that specifically normalize overt BACE1 activity around plaques. The microtubule-associated protein tau regulates axonal transport of proteins, and tau deletion rescues Aß-induced transport deficits in vitro. In the current study, long-term in vivo two-photon microscopy and immunohistochemistry were performed in tau-deficient APPPS1 mice. Tau deletion reduced plaque-associated axonal pathology and BACE1 accumulation without affecting physiological BACE1 expression distant from plaques. Thereby, tau deletion effectively decelerated formation of new plaques and reduced plaque compactness. The data revealed that tau reinforces Aß deposition, presumably by contributing to accumulation of BACE1 in plaque-associated dystrophies. Targeting tau-dependent mechanisms could become a suitable strategy to specifically reduce overt BACE1 activity around plaques, thereby avoiding adverse effects of systemic BACE inhibition.


Assuntos
Doença de Alzheimer/prevenção & controle , Secretases da Proteína Precursora do Amiloide/fisiologia , Ácido Aspártico Endopeptidases/antagonistas & inibidores , Regulação da Expressão Gênica , Placa Amiloide/prevenção & controle , Proteínas tau/antagonistas & inibidores , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/genética , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases/genética , Ácido Aspártico Endopeptidases/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/etiologia , Placa Amiloide/metabolismo , Placa Amiloide/patologia
4.
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
5.
Biosens Bioelectron ; 143: 111561, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31446202

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with severe memory loss and impaired cognitive skills. A common pathological change found in AD-affected brains is the accumulation of a peptide named amyloid-ß (Aß) that can form plaques. Aß aggregates are visible to structural scanning tools; however, these bulky and expensive instruments are accessible to trained personnel in clinical settings only, thus hampering timely diagnosis of the disease, particularly in low-resource settings. In this work, we design an organic electrochemical transistor (OECT) for in vitro detection of Aß aggregates in human serum. The OECT channel is integrated with a nanostructured isoporous membrane which has a strong affinity for Aß aggregates. The detection mechanism relies on the membrane capturing Aß aggregates larger than the size of its pores and thus blocking the penetration of electrolyte ions into the channel underneath. Combining the high transconductance of the OECT with the precise porosity and selectivity of the membrane, the device detects the presence of Aß aggregates in human serum samples with excellent sensitivity. This is the first-time demonstration of a biofunctionalized, nanostructured, and isoporous membrane integrated with a high-performance transistor for biosensing. This robust, low-power, non-invasive, and miniaturized sensor aids in the development of point-of-care tools for early diagnosis of AD.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/sangue , Peptídeos beta-Amiloides/isolamento & purificação , Técnicas Biossensoriais , Doença de Alzheimer/sangue , Encéfalo/metabolismo , Encéfalo/patologia , Humanos , Membranas Artificiais , Nanoestruturas/química , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Transistores Eletrônicos
6.
Nat Rev Neurol ; 15(9): 501-518, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31367008

RESUMO

Polymorphism in the apolipoprotein E (APOE) gene is a major genetic risk determinant of late-onset Alzheimer disease (AD), with the APOE*ε4 allele conferring an increased risk and the APOE*ε2 allele conferring a decreased risk relative to the common APOE*ε3 allele. Strong evidence from clinical and basic research suggests that a major pathway by which APOE4 increases the risk of AD is by driving earlier and more abundant amyloid pathology in the brains of APOE*ε4 carriers. The number of amyloid-ß (Aß)-dependent and Aß-independent pathways that are known to be differentially modulated by APOE isoforms is increasing. For example, evidence is accumulating that APOE influences tau pathology, tau-mediated neurodegeneration and microglial responses to AD-related pathologies. In addition, APOE4 is either pathogenic or shows reduced efficiency in multiple brain homeostatic pathways, including lipid transport, synaptic integrity and plasticity, glucose metabolism and cerebrovascular function. Here, we review the recent progress in clinical and basic research into the role of APOE in AD pathogenesis. We also discuss how APOE can be targeted for AD therapy using a precision medicine approach.


Assuntos
Doença de Alzheimer , Apolipoproteínas E/genética , Encéfalo/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides/metabolismo , Predisposição Genética para Doença , Humanos , Placa Amiloide/patologia , Polimorfismo Genético
7.
Orv Hetil ; 160(33): 1289-1295, 2019 Aug.
Artigo em Húngaro | MEDLINE | ID: mdl-31401858

RESUMO

The ever-growing average age of the society significantly increases the occurrence of Alzheimer's disease. The increased prevalence represents considerable social and economic burden, which urges the development of diagnostic and therapeutic methods in the field. The most common cause of dementia is Alzheimer's disease, the typical histopathological abnormality of which are well known. The detection of functional changes results in the early diagnosis of the disease, which precedes the morphological changes by years. Positron-emission tomography plays an important role in the demonstration of metabolic changes. The glucose metabolic pattern differs significantly in each clinical form of dementia. The most important ß-amyloid-binding radiopharmaceuticals that should be highlighted are [11C]Pittsburgh compound B that is widely used in the research and [18F]florbetapir that is commonly approved in diagnostics. Tracers visualising neurofibrillary tangles consisting of tau protein appeared most recently. The development continues; newer and newer radiopharmaceuticals appear. These tracers play an important role in both the research and the diagnostics. Orv Hetil. 2019; 160(33): 1289-1295.


Assuntos
Doença de Alzheimer/diagnóstico por imagem , Peptídeos beta-Amiloides/metabolismo , Encéfalo/diagnóstico por imagem , Imagem Molecular , Emaranhados Neurofibrilares/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Proteínas tau/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Progressão da Doença , Humanos , Emaranhados Neurofibrilares/patologia , Placa Amiloide/diagnóstico por imagem , Placa Amiloide/metabolismo , Placa Amiloide/patologia
8.
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
9.
Neurology ; 93(8): e778-e790, 2019 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-31320469

RESUMO

OBJECTIVE: To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease. METHODS: Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models. RESULTS: In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of APOE ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline. CONCLUSION: We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.


Assuntos
Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Cognição , Demência/patologia , Demência/psicologia , Fatores Etários , Idoso , Doença de Alzheimer/complicações , Doença de Alzheimer/diagnóstico , Demência/complicações , Progressão da Doença , Feminino , Humanos , Masculino , Emaranhados Neurofibrilares/patologia , Testes Neuropsicológicos , Placa Amiloide/patologia , Fatores de Risco , Fatores Sexuais
10.
Nat Neurosci ; 22(8): 1258-1268, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308530

RESUMO

The deposition of aggregated amyloid-ß peptides derived from the pro-amyloidogenic processing of the amyloid precurson protein (APP) into characteristic amyloid plaques (APs) is distinctive to Alzheimer's disease (AD). Alternative APP processing via the metalloprotease ADAM10 prevents amyloid-ß formation. We tested whether downregulation of ADAM10 activity by its secreted endogenous inhibitor secreted-frizzled-related protein 1 (SFRP1) is a common trait of sporadic AD. We demonstrate that SFRP1 is significantly increased in the brain and cerebrospinal fluid of patients with AD, accumulates in APs and binds to amyloid-ß, hindering amyloid-ß protofibril formation. Sfrp1 overexpression in an AD-like mouse model anticipates the appearance of APs and dystrophic neurites, whereas its genetic inactivation or the infusion of α-SFRP1-neutralizing antibodies favors non-amyloidogenic APP processing. Decreased Sfrp1 function lowers AP accumulation, improves AD-related histopathological traits and prevents long-term potentiation loss and cognitive deficits. Our study unveils SFRP1 as a crucial player in AD pathogenesis and a promising AD therapeutic target.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteína ADAM10/biossíntese , Proteína ADAM10/genética , Doença de Alzheimer/patologia , Secretases da Proteína Precursora do Amiloide/biossíntese , Secretases da Proteína Precursora do Amiloide/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Anticorpos Bloqueadores/uso terapêutico , Química Encefálica/genética , Regulação para Baixo , Humanos , Potenciação de Longa Duração , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/biossíntese , Camundongos , Camundongos Transgênicos , Neuritos/patologia , Placa Amiloide/tratamento farmacológico , Placa Amiloide/genética , Placa Amiloide/patologia
16.
Clin Nucl Med ; 44(7): 587-588, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31135517

RESUMO

Previous studies have reported increased Pittsburgh compound-B (PiB) uptake in meningiomas; however, histological correlation to elucidate the underlying mechanism has not yet been done. We report a case of an 82-year-old woman with an incidental intracranial tumor that showed focal increased PiB uptake. Because of tumor growth, surgical resection was performed, yielding a histological diagnosis of meningioma. Any special and immunochemical staining for amyloid did not reveal amyloid deposition in the tumor. Our findings suggest that increased PiB uptake was not associated with amyloid in this instance.


Assuntos
Neoplasias Meníngeas/diagnóstico por imagem , Meningioma/diagnóstico por imagem , Placa Amiloide/diagnóstico por imagem , Idoso de 80 Anos ou mais , Compostos de Anilina , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Neoplasias Meníngeas/patologia , Meningioma/patologia , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tiazóis
17.
Int J Mol Sci ; 20(9)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071995

RESUMO

Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aß peptide in amyloid plaques in Alzheimer's disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer's disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE-Αß complex. Our in vitro biophysical results prove that apoE peptide-analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE-Αß complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αß; taking an important step forward in the field of Alzheimer's anti-aggregation drug development.


Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Amiloidose/genética , Apolipoproteínas E/química , Doença de Alzheimer/patologia , Amiloide/química , Amiloide/genética , Amiloide/ultraestrutura , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/ultraestrutura , Amiloidose/patologia , Apolipoproteínas E/ultraestrutura , Sítios de Ligação , Colesterol/química , Colesterol/genética , Humanos , Placa Amiloide/genética , Placa Amiloide/patologia , Placa Amiloide/ultraestrutura , Agregação Patológica de Proteínas/genética , Agregação Patológica de Proteínas/patologia , Dobramento de Proteína , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/ultraestrutura
18.
EBioMedicine ; 43: 424-434, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31085101

RESUMO

BACKGROUND: The delivery of therapeutic proteins to selected sites within the central nervous system (CNS) parenchyma is a major challenge in the treatment of various neurodegenerative disorders. As brain-derived neurotrophic factor (BDNF) is reduced in the brain of people with Alzheimer's disease (AD) and its administration has shown promising therapeutic effects in mouse model of the disease, we generated a novel platform for T cell-based BDNF delivery into the brain parenchyma. METHODS: We generated amyloid beta-protein (Aß)-specific CD4 T cells (Aß-T cells), genetically engineered to express BDNF, and injected them intracerebroventricularly into the 5XFAD mouse model of AD. FINDINGS: The BDNF-secreting Aß-T cells migrated efficiently to amyloid plaques, where they significantly increased the levels of BDNF, its receptor TrkB, and various synaptic proteins known to be reduced in AD. Furthermore, the injected mice demonstrated reduced levels of beta-secretase 1 (BACE1)-a protease essential in the cleavage process of the amyloid precursor protein-and ameliorated amyloid pathology and inflammation within the brain parenchyma. INTERPRETATION: A T cell-based delivery of proteins into the brain can serve as a platform to modulate neurotoxic inflammation and to promote neuronal repair in neurodegenerative diseases.


Assuntos
Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/imunologia , Peptídeos beta-Amiloides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/patologia , Animais , Biomarcadores , Encéfalo/imunologia , Encéfalo/metabolismo , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Epitopos de Linfócito T/imunologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Transgênicos , Placa Amiloide/genética , Placa Amiloide/metabolismo , Placa Amiloide/patologia , Células Piramidais/imunologia , Células Piramidais/metabolismo , Células Piramidais/patologia , Especificidade do Receptor de Antígeno de Linfócitos T , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
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.
Neuroscience ; 409: 152-161, 2019 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-31034974

RESUMO

Axonopathy manifested by axon swellings might constitute one of the earliest pathological features of Alzheimer's disease. It has been proposed that axonopathy might be associated with the origin of Aß plaques. However, how axonopathy leads to Aß plaque pathogenesis remains elusive. Our previous studies have shown that Aß neuropathology (mainly diffuse plaques) selectively occurred in the regions of corticospinal tract (CST) pathway and its innervated region in the spinal cord of TgCRND8 mice. In this study, we investigated the occurrence and progression of axonopathy and the possible implication in Aß plaque pathogenesis in the spinal cord of TgCRND8 mice. By anterograde labeling of CST system with a neuroanatomical tracer, we found that dilated corticospinal axons started to appear at 7 months, then exhibited an age-dependent increase. These abnormal structures appear before any plaque deposits are visible in the spinal cord of the mice. Importantly, they colocalized with Aß plaques in either the white matter or gray matter of the spinal cord at later stages, suggesting that these axonal swellings might represent the initial stages of Aß plaque formation, and could play a role in Aß plaque pathogenesis. Furthermore, using ultrastructural analysis we demonstrated that intracellular contents in the axonal dystrophies such as various dense vesicles leaked out into the extracellular matrix under a condition of axon swelling rupture in CST pathways of spinal cord. This provided precise structural evidence that how the Aß leaks out from the axonal dystrophies into extracellular matrix and how an axonal swelling might serve as a nidus of amyloid plaque formation.


Assuntos
Doença de Alzheimer/patologia , Axônios/patologia , Placa Amiloide/patologia , Medula Espinal/patologia , Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Substância Cinzenta/patologia , Camundongos , Camundongos Transgênicos , Tratos Piramidais/patologia , Substância Branca/patologia
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