Altered gene expression and neuropathology in Alzheimer's disease

Abstract

0 d nd results from studies which have focused on alterations n gene expression in AD, performed both on postmortem rains from patients with AD and controls as well as on transenic mouse models of this disease. Their major conclusion s that findings from studies carried out to date on alterations n gene expression in AD are still limited in terms of their tility in treating AD patients and in developing early methds of detection. We generally agree with most of the ideas nd trajectories of Reddy and McWeeney [22]. However, we ould like to draw attention to the following issues. Firstly, several transgenic mouse models have proven aluable for modeling various aspects of the neuropatholgy of AD and associated cognitive changes (for review see 5,12,13,31]). As pointed out by Reddy and McWeeney [22], o mouse model developed up to now has recapitulated the ntire spectrum of human AD neuropathology. This has to e considered when interpreting results of gene expression months of age [28]. Neuron loss was observed at sites of A aggregation (in line with suggestions by [30]) and surrounding astrocytes but, most importantly, was also clearly observed in brain areas distant from plaques [28]. A comprehensive discussion of the potential differences between these APP751SL/PS1M146L mice and other transgenic mouse models of AD (including those mentioned by Reddy and McWeeney [22]) has been provided in [8]. Furthermore, APP751SL/PS1KI mice (mice transgenic for the aforementioned APP mutations and expressing human PS1 mutations [M233T and L235P] knocked-in into the mouse PS1 gene) show substantial neuron loss in hippocampal area CA1/2 by 50% on average already at 10 months of age [6]. Interestingly, the average amount of A aggregation was only 4.1% (v/v) in hippocampal area CA1/2 of these mice [6]. These data clearly demonstrated that in certain transgenic and knock-in mouse models of AD, neuron loss occurs in relation to sites of A tudies on mouse models of AD, since the impact of such tudies on the elucidation of mechanisms in the etiopathoenesis of AD is directly linked to the question how well he model actually reflects the neuropathology of AD. In this egard, however, Reddy and McWeeney’s [22] statement that aggregation but also independent on A aggregation. Additional molecular and histological analyses have confirmed the critical role of intraneuronal A 42 in neuron loss in these transgenic and knock-in mouse models of AD [4,6,28]. Overall, these findings have prompted important modifications of t m b R m o f F he transgenic mouse models of AD developed, so far, do ot mimic AD in the formation of neurofibrillary tangles and euronal loss should be taken cautiously. This is due to the act that the recently developed APP751SL/PS1M146L mice transgenic mice expressing both human mutant APP751 car-