. Lowering beta-amyloid levels rescues learning and memory in a Down syndrome mouse model. PLoS One. 2010;5(6):e10943. PubMed.


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  1. Some papers are especially admirable for their combination of simplicity and significance. Such is the case of the recent report by Netzer and colleagues who show that a γ-secretase inhibitor restores cognitive function in a mouse model of Down syndrome. All trisomy 21/DS individuals develop AD pathology by age 30-40 and usually exhibit AD-like cognitive deficits by age 50. We and others have also shown that all AD individuals harbor trisomy 21 cells in their brains and other tissues and, most recently, that Aβ can induce microtubule defects leading to chromosome mis-segregation and aneuploidy including trisomy 21 (Granic et al., 2009). Thus, AD and DS are intimately linked at many levels.

    Because the APP gene resides on chromosome 21, it has been assumed that the extra copy of chromosome 21 in DS underlies the development of AD in these individuals. This inference was strongly supported by the finding of families with inherited, early-onset Alzheimer disease caused by the mere duplication of the APP gene region on one chromosome 21 (Sleegers et al., 2006; Rovelet-Lecrux, 2006). However, which parts of chromosome 21 are responsible for the developmental, including cognitive, alterations observed in young DS individuals is unknown and the subject of much research. Many genes, including S100β, APP, Ncam2, and Dyrk1a, have both logical and experimental arguments in favor of their involvement in the cognitive deficits in DS (for discussion, see Belichenko et al., 2007). However, further defining the Down syndrome critical region (DSCR) or the mental retardation (MR) critical region has been difficult. Work with DS patients with partial trisomy 21 due to chromosome translocation has suggested that there is no single DSCR responsible for all of the features of DS or even one region responsible for MR (Korenberg et al., 2004; Belichenko et al., 2007). One approach to investigating the genetic causes of DS is to develop mice that by virtue of either a translocation or Cre-lox directed recombination and deletion carry three, or zero copies of parts of mouse chromosome 16. For example, the mouse that Netzer and colleagues used, Ts65Dn, is the classic mouse trisomy 16 model of DS which carries three copies of 13Mb (~33 genes) at the end of mouse chromosome 16, corresponding to much of human chromosome 21. Although this mouse recapitulates many of the physical and cognitive features of DS, whether the whole region or smaller parts of it are necessary or sufficient is still debated. One group created transgenic mice with a smaller cohort of triplicated genes than in Ts65Dn and found that triplicating this region was not sufficient to cause cognitive deficits including hippocampal deficits shown by the Morris water maze, but that making that particular region disomic in a Ts65Dn background restored hippocampal learning to normal, indicating that it was necessary for this behavior (Olson et al., 2007). In contrast, another group using different mice and somewhat different tasks showed that a similar region of chromosome 16 was sufficient to confer cognitive deficits (Belichenko et al., 2009).

    These studies make it both exciting and surprising that Netzer and colleagues found that suppressing the product (Aβ) of one gene (APP) in the DSCR by a γ-secretase inhibitor is sufficient to restore cognitive function in the Ts65Dn mouse model of AD. There are several possible explanations for this finding beyond the simple conclusion that Aβ is solely responsible for the MR of DS. To us, the most likely is that in mice, Aβ plays a critical role in microtubule function, and that too much (or maybe even too little) changes MT-dependent localization of key receptors (see, e.g., Abisambra et al., 2010). Alternatively, the inhibitor DAPT may have more extensive beneficial effects than only reducing Aβ production. Finally, the mouse models of neurological disease may be inherently easier to “cure” with pharmacological interventions than would be expected from the genetics underlying the human or the mouse phenotype. This latter possibility is most concerning because it might also explain why so many drugs that are effective in mouse models of AD turn out to be less or not effective in human trials. We may be facing a need to develop more robust assays of mouse behavior that cannot be modified by small changes in synaptic strength.


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