Dataset Information

Innate immune activation in Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is known as the most predominant cause of dementia among the aged people. Previously, two hallmarks of AD pathology including extracellular amyloid-? (A?) deposition and neurofibrillary tangles (NFTs) inside neurons have been identified. With a better understanding of this disease, neuroinflammation has been a focus, and as its initial event, innate immune activation plays an indispensable role. In brain, as an endogenous stimulator, extracellular A? deposition activates innate immunity through binding to the pattern recognition receptors (PRR), thus leading to the production and release of substantial inflammatory mediators (NO and ROS) and cytokines (IL-1?, IL-10, IL-33 and TNF-?) contributing to the development of AD. Epidemiologic evidence has suggested an affirmative influence of non-steroidal anti-inflammatory drugs (NSAIDs) on delaying the progression of AD. Therefore, blocking the inflammatory process may be an effective way to delay or even cure AD. In this review, we mainly elucidate the mechanism underlying these immune responses in AD pathogenesis and attempt to seek the therapeutic methods targeting neuroinflammation.

SUBMITTER: Wang MM

PROVIDER: S-EPMC5994517 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Innate immune activation in Alzheimer's disease.

Wang Ming-Ming MM Miao Dan D Cao Xi-Peng XP Tan Lin L Tan Lan L

Annals of translational medicine 20180501 10

Alzheimer's disease (AD) is known as the most predominant cause of dementia among the aged people. Previously, two hallmarks of AD pathology including extracellular amyloid-β (Aβ) deposition and neurofibrillary tangles (NFTs) inside neurons have been identified. With a better understanding of this disease, neuroinflammation has been a focus, and as its initial event, innate immune activation plays an indispensable role. In brain, as an endogenous stimulator, extracellular Aβ deposition activates ...[more]

PMID: 29951499

Similar Datasets

Project description:BackgroundAfter decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer's disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-L-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms.MethodsFreshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA.ResultsTreatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD.ConclusionsHere we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

Dataset Information

Innate immune activation in Alzheimer's disease.

Publications

Innate immune activation in Alzheimer's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets