Article

Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice

Department of Neurology, University of Münster, 48149 Münster, Germany.
Journal of Neuroinflammation (Impact Factor: 4.9). 10/2005; 2:22. DOI: 10.1186/1742-2094-2-22
Source: PubMed

ABSTRACT Inflammation is suspected to contribute to the progression and severity of neurodegeneration in Alzheimer's disease (AD). Transgenic mice overexpressing the london mutant of amyloid precursor protein, APP [V717I], robustly recapitulate the amyloid pathology of AD.
Early and late, temporal and spatial characteristics of inflammation were studied in APP [V717I] mice at 3 and 16 month of age. Glial activation and expression of inflammatory markers were determined by immunohistochemistry and RT-PCR. Amyloid deposition was assessed by immunohistochemistry, thioflavine S staining and western blot experiments. BACE1 activity was detected in brain lysates and in situ using the BACE1 activity kit from R&D Systems, Wiesbaden, Germany.
Foci of activated micro- and astroglia were already detected at age 3 months, before any amyloid deposition. Inflammation parameters comprised increased mRNA levels coding for interleukin-1beta, interleukin-6, major histocompatibility complex II and macrophage-colony-stimulating-factor-receptor. Foci of CD11b-positive microglia expressed these cytokines and were neighbored by activated astrocytes. Remarkably, beta-secretase (BACE1) mRNA, neuronal BACE1 protein at sites of focal inflammation and total BACE1 enzyme activity were increased in 3 month old APP transgenic mice, relative to age-matched non-transgenic mice. In aged APP transgenic mice, the mRNA of all inflammatory markers analysed was increased, accompanied by astroglial iNOS expression and NO-dependent peroxynitrite release, and with glial activation near almost all diffuse and senile Abeta deposits.
The early and focal glial activation, in conjunction with upregulated BACE1 mRNA, protein and activity in the presence of its substrate APP, is proposed to represent the earliest sites of amyloid deposition, likely evolving into amyloid plaques.

Download full-text

Full-text

Available from: Jochen Walter, Jun 29, 2015
0 Followers
 · 
328 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders such as Alzheimer's disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere shortening represent suitable and promising targets. Several studies show that cellular senescence is tightly interconnected to aging and AD, while the role of telomere dynamic and stability in AD pathogenesis is still unclear. This review will focus on the linking mechanisms between cellular senescence, telomere shortening and AD. Copyright © 2015. Published by Elsevier B.V.
    Ageing Research Reviews 04/2015; 22. DOI:10.1016/j.arr.2015.04.003 · 7.63 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Abstract Neurodegenerative diseases, which affect almost exclusively humans, are chronic disorders that ultimately result in atrophy of the brain and profound cognitive deficit. Neurodegenerative process reflects a profound failure of brain homeostasis. Neuroglial cells, being primarily the cells responsible for brain homeostasis and defense, naturally contribute to an overall homeostatic failure underlying neurodegeneration. In this chapter we shall deliver a brief on astroglial contribution to common neurodegenerative disorders and then continue with a detailed account on the pathological potential of astroglia in Alzheimer’s disease. Astrocytes undergo complex alterations in Alzheimer’s disease, which are represented by region-specific atrophy and asthenia at the early stages and reactivity at the late stages of the disease. These complex changes can be considered as pathologically relevant because they may define the early cognitive deficits and the later neurotoxicity in Alzheimer’s disease. Targeting astroglia in neurodegeneration may result in new therapeutic strategies aimed at preventing and delaying the progression of Alzheimer’s disease.
    Pathological Potential of Neuroglia. Possible New Targets for Medical Intervention, Edited by Alexei Verkhratsky, Vladimir Parpura, 09/2014: chapter Neurodegeneration and Neuroglia: Emphasis on Astroglia in Alzheimer’s Disease: pages 265 - 292; Springer., ISBN: 978-1-4939-0973-5
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neuroinflammation is a constant event in Alzheimer's disease (AD), but the current knowledge is insufficient to state whether inflammation is a cause, a promoter, or simply a secondary phenomenon in this inexorably progressive ailment. In the current paper, we review research data showing that inflammation is not a prerequisite for onset of dementia, and, although it may worsen the course of the disease, recent evidence shows that chronic inhibition of inflammatory pathways is not necessarily beneficial for patients. Prospective clinical trials with anti-inflammatory drugs failed to stop disease progression, measurements of inflammatory markers in serum and cerebrospinal fluid of patients yielded contradictory results, and recent bench research proved undoubtedly that neuroinflammation has a protective side as well. Knockout animal models for TNFRs or ILRs do not seem to prevent the pathology or the cognitive decline, but quite the contrary. In AD, the therapeutic intervention on inflammatory pathways still has a research future, but its targets probably need reevaluation.
    06/2013; 2013:316495. DOI:10.1155/2013/316495