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Soluble amyloid-? oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-? peptide (A?) as the major component of the amyloid plaques that are characteristically found in AD brains, a major effort has aimed to determine whether and how A? leads to memory loss and cognitive impairment. A large body of evidence accumulated in the past 15 years supports a pivotal role of soluble A? oligomers (A?Os) in synapse failure and neuronal dysfunction in AD. Nonetheless, a number of basic questions, including the exact molecular composition of the synaptotoxic oligomers, the identity of the receptor(s) to which they bind, and the signaling pathways that ultimately lead to synapse failure, remain to be definitively answered. Here, we discuss recent advances that have illuminated our understanding of the chemical nature of the toxic species and the deleterious impact they have on synapses, and have culminated in the proposal of an A? oligomer hypothesis for Alzheimer's pathogenesis. We also highlight outstanding questions and challenges in AD research that should be addressed to allow translation of research findings into effective AD therapies.

SUBMITTER: Ferreira ST

PROVIDER: S-EPMC4443025 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease.

Ferreira Sergio T ST Lourenco Mychael V MV Oliveira Mauricio M MM De Felice Fernanda G FG

Frontiers in cellular neuroscience 20150526

Alzheimer's disease (AD) is the most common form of dementia in the elderly, and affects millions of people worldwide. As the number of AD cases continues to increase in both developed and developing countries, finding therapies that effectively halt or reverse disease progression constitutes a major research and public health challenge. Since the identification of the amyloid-β peptide (Aβ) as the major component of the amyloid plaques that are characteristically found in AD brains, a major eff ...[more]

PMID: 26074767

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Project description:To identify epigenetically regulated genes involved in the pathogenesis of Alzheimer's disease (AD) we analyzed global mRNA expression and methylation profiles in amyloid precursor protein (APP)-Swedish mutant-expressing AD model cells, H4-sw and selected heme oxygenase-1 (HMOX1), which is associated with pathological features of AD such as neurofibrillary tangles and senile plaques. We examined the epigenetic regulatory mechanism of HMOX1 and its application as a diagnostic and prognostic biomarker for AD. Our results show that HMOX1 mRNA and protein expression was approximately 12.2-fold and 7.9-fold increased in H4-sw cells, respectively. Increased HMOX1 expression was also detected in the brain, particularly the hippocampus, of AD model transgenic mice. However, the methylation of specific CpG sites within its promoter, particularly at CpG located -374 was significantly decreased in H4-sw cells. Treatment of neuroglioma cells with the demethylating agent 5-aza-2'-deoxycytidine resulted in reduced methylation of HMOX1 promoter accompanied by enhanced HMOX1 expression strongly supporting DNA methylation-dependent transcriptional regulation of HMOX1. Toxic Aβ-induced aberrant hypomethylation of HMOX1 at -374 promoter CpG site was correlated with increased HMOX1 expression. In addition to neuroglioma cells, we also found Aβ-induced epigenetic regulation of HMOX1 in human T lymphocyte Jurkat cells. We evaluated DNA methylation status of HMOX1 at -374 promoter CpG site in blood samples from AD patients, patients with mild cognitive impairment (MCI), and control individuals using quantitative methylation-specific polymerase chain reaction. We observed lower methylation of HMOX1 at the -374 promoter CpG site in AD patients compared to MCI and control individuals, and a correlation between Mini-Mental State Examination score and demethylation level. Receiver operating characteristics analysis revealed good discrimination of AD patients from MCI patients and control individuals. Our findings suggest that the methylation status of HMOX1 at a specific promoter CpG site is related to AD progression.

Project description:BackgroundThe increasing incidence of cognitive impairment has become a health problem in the aging society. Owing to its antioxidant and anti-inflammatory properties, Brazilian green propolis-derived from Baccharis dracunculifolia-is anticipated to possess anticognitive properties. However, the preventive effect of Brazilian green propolis on cognitive impairment remains unexplained. This study aimed to investigate the effect of Brazilian green propolis on cognitive impairment using a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular injection of amyloid beta (Aβ)25‒35.MethodsFive-week-old male Slc:ddY mice were randomly divided into five groups (n = 8). The groups were pretreated with vehicle and propolis at a dose of 100, 300 and 900 mg/kg body weight for 8 days, then AD-like phenotypes were induced by intracerebroventricular (ICV) injection of Aβ25‒35. A sham operation group was set as the control. Memory and learning ability were measured at 7 to 8 days after ICV injection. Gene expression and histological studies were performed at the endpoint of the study.ResultsIn a passive avoidance test, the administration of Brazilian green propolis prevented the impairment of learning and memory function. Furthermore, comprehensive gene expression analysis in the hippocampus and forebrain cortex revealed that Brazilian green propolis suppressed Aβ25-35-induced inflammatory and immune responses. In particular, Brazilian green propolis prevented alterations in gene expressions of microglial and astrocytic markers such as Trem2 and Lcn2 induced by Aβ25‒35 injection, suggesting the suppression of excessive activation of glial cells in the brain. In addition, Brazilian green propolis suppressed the elevation of plasma interleukin (IL)-6 levels induced by Aβ25‒35 injection.ConclusionsThe results suggest that the prophylactic administration of Brazilian green propolis has a preventive effect against AD by suppressing excessive inflammation and immune response in glial cells. To our knowledge, this study is the first to demonstrate that Brazilian green propolis may inhibit the hyperactivation of microglia and astrocytes as a mechanism of action to prevent AD. Thus, it is a promising ingredient for preventing AD-type dementia.

Dataset Information

Soluble amyloid-? oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease.

Publications

Soluble amyloid-β oligomers as synaptotoxins leading to cognitive impairment in Alzheimer's disease.

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