. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci. 2007 Feb 21;27(8):1981-91. PubMed.

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  1. My initial enthusiasm, shared with commentator Tom Fagan, for this study was cooled when I tried to discover which dominant-negative mutant of GSK3β was used. The answer appears to be "none" since wild-type GSK3β was incorporated in the injected DNA construct (see materials & methods section, page 1982). Hence, overexpression of wild-type GSK3β decreases GSK3 enzyme activity in brain....

    I noticed this rather "uncommon" outcome of a transgenic mouse while attending the AD-PD meeting in Salzburg (although time to read was scarce) and discussed the matter with several "knowledgeable" colleagues. We failed to come up with an acceptable explanation and were not satisfied with the one provided in the paper. Indeed, when GSK3 activity is downregulated by activated Akt and phosphorylation of S9, that would restore (or even lower more) Akt activity…and a futile cycle would result.

    We were therefore wondering if the transgenic construct is correct—i.e., an unnoticed mutation slipped in during PCR?—or whether the enzymatic assay provided the correct answers, since it is known to be a very tricky procedure. On the other hand, if indeed the GSK3β activity is down in these mice, the cause could also be due to genetic regulation and/or integration site effects, which will be more difficult to "un-tangle" (to maintain the jargon of this field)!

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