White JA, Manelli AM, Holmberg KH, et al. Differential effects of oligomeric and fibrillar amyloid-beta 1-42 on astrocyte-mediated inflammation

Department of Medicine, Division of Geriatrics, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA.
Neurobiology of Disease (Impact Factor: 5.08). 05/2005; 18(3):459-65. DOI: 10.1016/j.nbd.2004.12.013
Source: PubMed


Activated glia, as a result of chronic inflammation, are associated with amyloid-beta peptide (Abeta) deposits in the brain of Alzheimer's disease (AD) patients. In vitro, glia are activated by Abeta inducing secretion of pro-inflammatory molecules. Recent studies have focused on soluble oligomers (or protofibrils) of Abeta as the toxic species in AD. In the present study, using rat astrocyte cultures, oligomeric Abeta induced initial high levels of IL-1beta decreasing over time and, in contrast, fibrillar Abeta increased IL-1beta levels over time. In addition, oligomeric Abeta, but not fibrillar Abeta, induced high levels of iNOS, NO, and TNF-alpha. Our results suggest that oligomers induced a profound, early inflammatory response, whereas fibrillar Abeta showed less increase of pro-inflammatory molecules, consistent with a more chronic form of inflammation.

Download full-text


Available from: Kristina H Holmberg,
  • Source
    • "Mixed glial cultures (95% astrocytes, 5% microglia) were isolated from APOE-TR and APOE-KO mice as described (White et al. 2005; Nwabuisi-Heath et al. 2012). Glial cultures (24-well plates) were incubated with oAb42 (0– 10 lM) (see Stine et al. 2003; White et al. 2005 for details) or LPS (0-100 ng/mL), +/À LPSRS, IAXO101, IAXO103, IAXO202 (Innaxon, Tewkesbury, UK), MW181 (Watterson et al. 2013, Bachstetter et al. 2014), or vehicle control, at the concentrations indicated in the figures (N.B. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic glial activation and neuroinflammation induced by the amyloid-β peptide (Aβ) contribute to Alzheimer's disease (AD) pathology. APOE4 is the greatest AD-genetic risk factor; increasing risk up to 12-fold compared to APOE3, with APOE4-specific neuroinflammation an important component of this risk. This editorial review discusses the role of APOE in inflammation and AD, via a literature review, presentation of novel data on Aβ-induced neuroinflammation, and discussion of future research directions. The complexity of chronic neuroinflammation, including multiple detrimental and beneficial effects occurring in a temporal and cell-specific manner, has resulted in conflicting functional data for virtually every inflammatory mediator. Defining a neuroinflammatory phenotype (NIP) is one way to address this issue, focusing on profiling the changes in inflammatory mediator expression during disease progression. Although many studies have shown that APOE4 induces a detrimental NIP in peripheral inflammation and Aβ-independent neuroinflammation, data for APOE-modulated Aβ-induced neuroinflammation are surprisingly limited. We present data supporting the hypothesis that impaired apoE4 function modulates Aβ-induced effects on inflammatory-receptor signaling, including amplification of detrimental (TLR4-p38α) and suppression of beneficial (IL-4R-nuclear receptor) pathways. To ultimately develop APOE genotype-specific therapeutics, it is critical that future studies define the dynamic NIP profile and pathways that underlie APOE-modulated chronic neuroinflammation. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of Neurochemistry 02/2015; 133(4). DOI:10.1111/jnc.13072 · 4.28 Impact Factor
  • Source
    • "There is evidence for differential induction of glial cell reactivity and functional states by oligomeric and fibrillar forms of A␤ [69] [70] [71]. For example, key functional pathways may be suppressed when the accumulation of fibrillar A␤ deposits reaches a certain level [70] and fibrillar A␤ may be associated with a hypocholinergic microenvironment [71]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cholinesterase enzymes metabolize acetylcholine (ACh). Inhibition of acetylcholinesterase (AChE) in damaged but functional cholinergic synapses in the brains of dementia patients increases intrasynaptic ACh. This enhances cholinergic neurotransmission and improves cognition. There is a window of opportunity for this symptomatic treatment effect that opens and closes during the course of dementia depending on when significant synaptic damage occurs. Cholinesterases also metabolize extrasynaptic ACh with butyrylcholinesterase (BuChE) apparently playing the major dynamic role in extracellular ACh homeostasis. Extracellular ACh plays a key regulatory role in controlling the reactivity and functional states of non-excitable cells, such as neuroglia. Current inhibitors of cholinesterases (ChEIs) have similar effects on intrasynaptic ACh, but differ markedly in abilities to upregulate extracellular AChE, inhibit BuChE, and influence the fibrilization of amyloid-β peptides. Importantly, ChEIs can have detrimental disease modifying effects in particular individuals characterized by age, gender, and genotype. In contrast, preliminary evidence suggests that the right dose of the right ChEI in the right patient might significantly slow the progression of neurodegenerative processes. For a particular patient, understanding the condition of cholinergic synapses and the reactivity and functional status of neuroglia could allow administration of appropriate ChEI therapy for symptomatic and disease modifying benefits.
    Journal of Alzheimer's disease: JAD 11/2014; 44(4). DOI:10.3233/JAD-142268 · 4.15 Impact Factor
  • Source
    • "A growing body of evidence from large-scale autopsy studies supports the notion that cerebrovascular dysfunction commonly co-occurs with, and likely interacts with, other neurobiological processes of aging. These studies suggest that among individuals who die clinically demented, a common autopsy finding is an admixture of cerebrovascular, Alzheimer, and Lewy body pathologies (Brayne et al. 2009; Schneider et al. 2007a; White et al. 2005a). Further studies suggest that each of the implicated pathologies may be clinically relevant to cognitive functioning; individuals with a certain level of a particular pathology at autopsy were more likely to have reduced cognitive functioning near the end of life when additional pathologies were also present at autopsy (Schneider et al. 2007b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: For some researchers, the relationship between prevalent cardiovascular risk factors and late-life cognitive decline is not worthy of further study. It is already known that effective treatment of vascular risk factors lowers risk of such major outcomes as stroke and heart attack, the argument goes; thus, any new information about the relationship between vascular risk factors and another major outcome - late-life cognitive decline-- is unlikely to have an impact on clinical practice. The purpose of this review is to probe the logic of this argument by focusing on what is known, and what is not known, about the relationship between vascular risk factors and late-life cognitive decline. The unknowns are substantial: in particular, there is relatively little evidence that current vascular risk factor treatment protocols are adequate to prevent late-life cognitive decline or the clinically silent brain injury that precedes it. In addition, there is relatively little understanding of which factors lead to differential vulnerability or resilience to the effects of vascular risk factors on silent brain injury. Differential effects of different classes of treatments are similarly unclear. Finally, there is limited understanding of the impact of clinically-silent neurodegenerative disease processes on cerebrovascular processes. Further study of the relationships among vascular risk factors, brain injury, and late-life cognitive decline could have a major impact on development of new vascular therapies and on clinical management of vascular risk factors, and there are promising avenues for future research in this direction.
    Neuropsychology Review 08/2014; 24(3). DOI:10.1007/s11065-014-9264-7 · 4.59 Impact Factor
Show more