. Impairments in fast axonal transport and motor neuron deficits in transgenic mice expressing familial Alzheimer's disease-linked mutant presenilin 1. J Neurosci. 2007 Jun 27;27(26):7011-20. PubMed.

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  1. This paper underscores the importance of impaired axonal transport and motor neuron deficits induced by familial mutations in PS1. We agree with the notion that the problem in AD is intraneuronal mistrafficking of different axonal proteins, and the results presented may explain some pathological features we have previously observed. We have studied two bigenic AD mouse models with abundant intraneuronal Aβ accumulation, which correlated well with the observed neuron loss, and axonal degeneration in brain and spinal cord. We agree with Lazarov et al. that these defects are likely induced by a different trafficking of APP due to expression of mutant PS1. In both models, the APP751SL/PS1M146L (Schmitz et al., 2004), and the APP/PS1KI (APP751SL and knock-in of PS1M233T and PS1L235P) (Casas et al., 2004) mouse model, we have shown that neuronal dysfunction is plaque-independent (Wirths et al., 2006a; Wirths et al., 2006b).

    The APP/PS1KI mouse model is especially interesting, because 50 percent of CA1 neurons are lost at 10 months of age (Casas et al., 2004). These mice also exhibit early and robust brain and spinal cord axonal degeneration, as shown by the occurrence of axonal spheroids, together with a reduced ability to perform motor performance tasks, including balance beam, string suspension, or rotarod. Working memory deficits were also evident at that time point (6 months of age) (Wirths et al., 2007). In good agreement with Lazarov et al. we have found evidence for increased levels of phosphorylated proteins (Tau [pS199] and APP [Thr668]) in degenerating axons inducing a loss of trophic support which might explain the robust age-dependent axonal degeneration in APP/PS1KI mice.

    References:

    . Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol. 2004 Oct;165(4):1289-300. PubMed.

    . Hippocampal neuron loss exceeds amyloid plaque load in a transgenic mouse model of Alzheimer's disease. Am J Pathol. 2004 Apr;164(4):1495-502. PubMed.

    . Age-dependent axonal degeneration in an Alzheimer mouse model. Neurobiol Aging. 2007 Nov;28(11):1689-99. PubMed.

    . Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease. Acta Neuropathol. 2006 Apr;111(4):312-9. PubMed.

    . Deficits in working memory and motor performance in the APP/PS1ki mouse model for Alzheimer's disease. Neurobiol Aging. 2008 Jun;29(6):891-901. PubMed.

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