. Pharmacotherapy for cognitive impairment in a mouse model of Down syndrome. Nat Neurosci. 2007 Apr;10(4):411-3. PubMed.

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  1. I'd like to put forward the hypothesis that Aβ may compete with pleiotrophin (heparin-binding growth associated molecule) for binding to VEGF165. Yang and colleagues (1) report that binding of Aβ to VEGF165 inhibits both Aβ-induced formation of reactive oxygen species and Aβ aggregation. Pleiotrophin is found to be upregulated on PTEN depletion and also enhances GABAA signaling (2,3). In view of the fact that presenilin-deficient cells and AD brain have reduced PTEN levels and pleiotrophin is found in amyloid plaques in AD and DS (4,5), it would seem we may expect amyloid deposition and enhanced GABAA signaling in both disease states. The study by Craig Garner and colleagues reporting normal cognition in their mouse model following the use of GABAA antagonists is most interesting and would seem to indicate benefit for those with AD as well. It will be interesting to see the results of the clinical trials. Perhaps the study by Nabekura et al. finding that DHA inhibits the GABA response may help to explain the cognitive benefit reported by Cole and Frautschy (6,7).

    Increased pleiotrophin is also reported in multiple myeloma (8). Should my hypothesis be correct, then you'd expect an increased incidence of dementia and AD associated with that disease. Maybe GABAA inhibition is also indicated with possible silencing of pleiotrophin as a first step.

    It's interesting that the Forkhead transcription factors FKHRL1 and FKHR are aberrantly localized to the cytoplasm and cannot activate transcription in PTEN-deficient cells and that inactivation of Rho/ROCK signaling is a prerequisite for FKHR nuclear translocation and myoblast fusion (9,10). This may explain part of the benefit of ROCK inhibition. Is incomplete myoblast fusion a feature of AD, and if so, may it explain the gait abnormalities? It's of interest that DYRK1A, which is upregulated in AD brain, phosphorylates tau and also FKHR and reduces FKHR accumulation in the nucleus (10,11).

    View all comments by Mary Reid
  2. It's of interest that Zhao and colleagues (1) found increased efflux of thiamine pyrophosphate in leukemia cells overexpressing the reduced folate carrier. The possibility of reduced cellular thiamine pyrophosphate in DS due to the overexpression of RFC1 is very intriguing. Dodd et al. (2) find increased GABAA and reduced NMDA binding sites in some brain areas in a goat model with thiamine deficiency. It would be interesting to see whether administration of thiamine pyrophosphate in the mouse model of DS would restore cognition as do the GABAA antagonists in the Garner study. Thiamine deficiency has been described as a rare cause of reversible pulmonary hypertension and it makes me wonder whether that might explain the increased risk of this disease as well as congenital ASD and VSD in the DS population (3).

    View all comments by Mary Reid

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