. Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease. J Neurosci. 2009 Aug 12;29(32):10144-52. PubMed.

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  1. One of the several interesting aspects of this study is the non-linear progression of the mutant PS1 phenotype with age. Although this generates more questions than answers, it points to the complexity of the system, leading myself and others to question if this middle-age response is the brain's attempt to compensate for underlying insults and/or metabolic stressors.

    We had observed somewhat of a parallel phenomenon in six-month-old PS1M146KI and 3xTg-AD mice, even though we were measuring different, but perhaps related, functions. In our study examining the effects of age on calcium signaling dysregulation in AD mice, we observed an apparent reduction in the increased ER calcium release, upregulation of RyR protein levels, and the IP3/calcium evoked K+ currents at the six-month time point, whereas at three months of age all these traits were grossly increased relative to Non-Tg controls and returned to these high/aberrant levels at 12 months.

    We are still not clear on the mechanisms involved in this dynamic shift over time, but this study by Auffret et al. demonstrates several other alterations occurring at this similar time point in mutant PS-expressing mice. Are these alterations compensatory? Clearly under the heading of “more studies are needed,” it is possible that this stage in the disease process reflects a “code blue” status which, in turn, recruits an array of neuroprotective responses, only to be overrun by pathogenic cascades eventually.

    References:

    . Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult, and aged Alzheimer's disease mice. J Neurosci. 2006 May 10;26(19):5180-9. PubMed.