Heneka, M.T. et al. Focal glial activation coincides with increased BACE1 activation and precedes amyloid plaque deposition in APP[V717I] transgenic mice. J. Neuroinflammation [online] 2, 22

Department of Neurology, University of Münster, 48149 Münster, Germany.
Journal of Neuroinflammation (Impact Factor: 5.41). 10/2005; 2(1):22. DOI: 10.1186/1742-2094-2-22
Source: PubMed


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.

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    • "Local groups of reactive astrocytes, for example, have been identified in the brain tissue of transgenic mice over-expressing the London mutant of the amyloid precursor protein, APP [V717I] long before any detectable ␤-amyloid depositions. These reactive astrocytes produce pro-inflammatory factors and up-regulate expression of inducible nitric oxide synthetase (iNOS), and arguably prepare ground for a senile plaques evolution (Heneka et al., 2005). Reactive GFAP-positive astrocytes, mainly associated with senile plaques and perivascular ␤-amyloid deposits, have been also observed in this transgenic model, as well as in other animal models of AD, such as 3xTg-AD mice harboring three mutant genes (␤-amyloid precursor, presenilin-1, and tau) (Verkhratsky., 2008). "
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    • "Local groups of reactive astrocytes, for example, have been identified in the brain parenchyma of transgenic mice over-expressing the London mutant of amyloid precursor protein, APP [V717I] long before any detectable b-amyloid depositions. These reactive astrocytes produced pro-inflammatory factors and up-regulated expression of inducible nitric oxide synthetase (iNOS), and arguably prepared the ground for future senile plaque evolution (Heneka et al., 2005). At the same time, in transgenic AD models such as 3xTg-AD (the triple transgenic mouse model of AD that harbors three mutant genes for the APPSwe, the PS1M146V and the tauP301L (Oddo et al. 2003a,b)), and in PDAPP-J20 mice (expressing mutant APP) morphological atrophy of astroglial cells also occurred early (see below), preceding an emergence of b-amyloid deposits and senile plaques (Olabarria et al., 2010; Yeh et al., 2011; Beauquis et al., 2013). "
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