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....  Read more

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:
Stutzmann GE, Smith I, Caccamo A, Oddo S, LaFerla FM, Parker I. (2006) Enhanced ryanodine receptor recruitment contributes to Ca2+ disruptions in young, adult and aged Alzheimer’s disease mice. Journal of Neuroscience, 26(20):5180-5189. Abstract

View all comments by Grace (Beth) Stutzmann

Bittner and colleagues succinctly describe the effects of gamma-secretase inhibition on dendritic spine density in the neocortex using in vivo, two-photon imaging in mice. The authors report that chronic, independent administration of two different gamma-secretase inhibitors reduces the density of synaptic spines in a focal region of neocortex, and that this effect requires the presence of APP.

These intriguing findings will certainly stimulate further research on this topic, as synapse loss could impair cognitive function in people treated with gamma secretase inhibitors, thus neutralizing potential benefits of the therapy in Alzheimer patients. This report raises several questions: 1) Is the anatomical distribution of the effect widespread or focal in the brain? (this issue might be addressed by biochemical or stereological analysis of synapse-associated markers); 2) what is the dose-response relationship between gamma secretase inhibition and synapse depletion, and is this phenomenon separable from the effect of the inhibitors on Aβ levels? and 3) a key issue, noted...  Read more

Bittner and colleagues succinctly describe the effects of gamma-secretase inhibition on dendritic spine density in the neocortex using in vivo, two-photon imaging in mice. The authors report that chronic, independent administration of two different gamma-secretase inhibitors reduces the density of synaptic spines in a focal region of neocortex, and that this effect requires the presence of APP.

These intriguing findings will certainly stimulate further research on this topic, as synapse loss could impair cognitive function in people treated with gamma secretase inhibitors, thus neutralizing potential benefits of the therapy in Alzheimer patients. This report raises several questions: 1) Is the anatomical distribution of the effect widespread or focal in the brain? (this issue might be addressed by biochemical or stereological analysis of synapse-associated markers); 2) what is the dose-response relationship between gamma secretase inhibition and synapse depletion, and is this phenomenon separable from the effect of the inhibitors on Aβ levels? and 3) a key issue, noted in the paper's Discussion, is whether chronic gamma secretase inhibition influences cognition, and whether the predicted behavioral changes persist following discontinuation of the drugs. The outcome of follow-up studies could influence strategic approaches to lowering Aβ in Alzheimer disease.

View all comments by Lary Walker