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      Genomic background-related activation of microglia and reduced β-amyloidosis in a mouse model of Alzheimer's disease

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          Alzheimer's disease (AD) is by far the most common neurodegenerative disease. AD is histologically characterized not only by extracellular senile plaques and vascular deposits consisting of β-amyloid (Aβ) but also by accompanying neuroinflammatory processes involving the brain's microglia. The importance of microglia is still in controversial discussion, which currently favors a protective function in disease progression. Recent findings by different research groups highlighted the importance of strain-specific and mitochondria-specific genomic variations in mouse models of cerebral β-amyloidosis. Here, we want to summarize our previously presented data and add new results that draw attention towards the consideration of strain-specific genomic alterations in the setting of APP transgenes. We present data from APP-transgenic mice in commonly used C57Bl/6J and FVB/N genomic backgrounds and show a direct influence on the kinetics of Aβ deposition and the activity of resident microglia. Plaque size, plaque deposition rate, and the total amount of Aβ are highest in C57Bl/6J mice as compared to the FVB/N genomic background, which can be explained at least partially by a reduced microglia activity toward amyloid deposits in the C57Bl/6J strain.

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          Most cited references 35

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          Activation of microglial cells by beta-amyloid protein and interferon-gamma.

           L Otvos,  P. Baron,  L Meda (1995)
          Alzheimer's disease is the most common cause of progressive intellectual failure. The lesions that develop, called senile plaques, are extracellular deposits principally composed of insoluble aggregates of beta-amyloid protein (A beta), infiltrated by reactive microglia and astrocytes. Although A beta, and a portion of it, the fragment 25-35 (A beta (25-35)), have been shown to exert a direct toxic effect on neurons, the role of microglia in such neuronal injury remains unclear. Here we report a synergistic effect between A beta and interferon-gamma (IFN-gamma) in triggering the production of reactive nitrogen intermediates and tumour-necrosis factor-alpha (TNF-alpha) from microglia. Furthermore, using co-culture experiments, we show that activation of microglia with IFN-gamma and A beta leads to neuronal cell injury in vitro. These findings suggest that A beta and IFN-gamma activate microglia to produce reactive nitrogen intermediates and TNF-alpha, and this may have a role in the pathogenesis of neuronal degeneration observed in ageing and Alzheimer's disease.
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            Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum?

            Amyloid beta (Abeta) is a small self-aggregating peptide produced at low levels by normal brain metabolism. In Alzheimer's disease (AD), self-aggregation of Abeta becomes rampant, manifested most strikingly as the amyloid fibrils of senile plaques. Because fibrils can kill neurons in culture, it has been argued that fibrils initiate the neurodegenerative cascades of AD. An emerging and different view, however, is that fibrils are not the only toxic form of Abeta, and perhaps not the neurotoxin that is most relevant to AD: small oligomers and protofibrils also have potent neurological activity. Immuno-neutralization of soluble Abeta-derived toxins might be the key to optimizing AD vaccines that are now on the horizon.
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              Formation and maintenance of Alzheimer's disease beta-amyloid plaques in the absence of microglia.

              In Alzheimer's disease, microglia cluster around beta-amyloid deposits, suggesting that these cells are important for amyloid plaque formation, maintenance and/or clearance. We crossed two distinct APP transgenic mouse strains with CD11b-HSVTK mice, in which nearly complete ablation of microglia was achieved for up to 4 weeks after ganciclovir application. Neither amyloid plaque formation and maintenance nor amyloid-associated neuritic dystrophy depended on the presence of microglia.

                Author and article information

                European Journal of Microbiology and Immunology
                Akadémiai Kiadó, co-published with Springer Science+Business Media B.V., Formerly Kluwer Academic Publishers B.V.
                1 March 2013
                : 3
                : 1
                : 21-27
                [ 1 ] Department of Neurology, Neurodegeneration Research Lab (NRL), University of Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
                [ 2 ] German Center for Neurodegenerative Diseases (DZNE) Magdeburg, Leipziger Str. 44, 39120, Magdeburg, Germany
                [ 3 ] Department of Behavioral Neurology, Leibniz Institute for Neurobiology (LIN), Brennecke Str. 6, 39118, Magdeburg, Germany
                [ 4 ] Department of Neurology, Neurodegeneration Research Laboratory (NRL), University of Magdeburg, Leipziger Str 44, Bldg 15, 39120, Magdeburg, Germany
                Author notes

                These authors contributed equally (in alphabetical order).

                [* ] +49 (391) 67 24514, +49 (391) 67 24528, jens.pahnke@ 123456gmail.com , www.NRL.ovgu.de


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