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William CM, Andermann ML, Goldey GJ, Roumis DK, Reid RC, Shatz CJ, Albers MW, Frosch MP, Hyman BT. Synaptic plasticity defect following visual deprivation in Alzheimer’s disease model transgenic mice. J Neurosci. 2012 June 6;32(23):8004-11.
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The current paper from Brad Hyman´s group very nicely shows that transgenic mice overexpressing FAD-mutated APP have reduced ocular dominance plasticity in the visual cortex. The data are very convincing as the study is carefully performed on two independent transgenic lines, applying two complementary methods assessing synaptic reorganisation after visual deprivation. Confounding effects of transgene expression on the basic spatial extent and laminar distribution of the visual cortex response to light or the overall responsiveness of the visual cortex have been ruled out, indicating that baseline functional organization of visual responses most unlikely account for the observed effects.
In line with recent evidence that NMDA signalling, a mechanism required for synaptic plasticity, can be affected by Aβ (e.g. Hsieh et al. Neuron 2006;52:831), it is very tempting to assume a causative role for Aβ in disrupting synaptic plasticity. Still, other explanations might be possible, and it would be interesting to compare those strains analysed in the present study with transgenic mice expressing human wild-type APP at a comparable level. This also might shed light on previous discrepant findings reporting decreased (Wegenast-Braun et al. 2009) or increased (Grinevich et al. 2009; Perez-Cruz et al. 2011) Arc expression in different APP mouse strains. Accordingly, a recent study by Seeger et al. (Neurobiol.Dis. 2009;35:258) has shown a synaptotrophic effect for transgenic wild-type APP, which is lost when FAD-mutated APP is overexpressed instead.
Irrespectively of the precise molecular mechanisms that account for the observed changes, the present study adds an important piece of evidence to the concept (e.g. Arendt; Neuroscience 2001;102:723) that a failure of synaptic reorganisation is of utmost importance in the AD pathomechanism. Realizing that Aβ and perhaps other fragments of APP might have an intrinsic role in making and reshaping our brain, the size of the challenge to interfere with these mechanisms with a therapeutic intention immediately becomes clear.
References:
Hsieh H, Boehm J, Sato C, Iwatsubo T, Tomita T, Sisodia S, Malinow R. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron. 2006 Dec 7;52(5):831-43. PubMed.
Wegenast-Braun BM, Fulgencio Maisch A, Eicke D, Radde R, Herzig MC, Staufenbiel M, Jucker M, Calhoun ME. Independent effects of intra- and extracellular Abeta on learning-related gene expression. Am J Pathol. 2009 Jul;175(1):271-82. PubMed.
Grinevich V, Kolleker A, Eliava M, Takada N, Takuma H, Fukazawa Y, Shigemoto R, Kuhl D, Waters J, Seeburg PH, Osten P. Fluorescent Arc/Arg3.1 indicator mice: a versatile tool to study brain activity changes in vitro and in vivo. J Neurosci Methods. 2009 Oct 30;184(1):25-36. Epub 2009 Jul 21 PubMed.
Perez-Cruz C, Nolte MW, van Gaalen MM, Rustay NR, Termont A, Tanghe A, Kirchhoff F, Ebert U. Reduced spine density in specific regions of CA1 pyramidal neurons in two transgenic mouse models of Alzheimer's disease. J Neurosci. 2011 Mar 9;31(10):3926-34. PubMed.
Seeger G, Gärtner U, Ueberham U, Rohn S, Arendt T. FAD-mutation of APP is associated with a loss of its synaptotrophic activity. Neurobiol Dis. 2009 Aug;35(2):258-63. PubMed.
Arendt T. Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization. Neuroscience. 2001;102(4):723-65. PubMed.
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