Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, Jucker M.
Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein.
Sci Transl Med. 2013 Jul 17;5(194):194re2.
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This is an excellent and carefully conducted study, with implications for extrapolating from transgenic mouse models to human Alzheimer's disease. By characterizing two different transgenic models, one with less-aggressive amyloid pathology, the authors could dissect the time course of changes in the cerebrospinal fluid and the brain. It appears that brain Aβ increases slightly before the drop in CSF Aβ42, and tau increases more or less at the same time. The authors did not present a time course of specific forms of Aβ (e.g., oligomers or plaques), and it would be interesting to see this superimposed. That tau is increased in mouse CSF is interesting, and suggests that there is a degree of damage, with release of tau from neurons or axons, i.e., tau may be a damage marker rather than a neurodegeneration marker—because of the absence of neurotic pathology or tangles in these models. It will be interesting to identify whether phosphorylated tau is also present in the CSF, and its time course.
There are some differences between the findings and the typical CSF biomarker profile in AD (including familial AD). First, the CSF Aβ42 levels continue to decrease and the tau levels continue to rise to five-fold above baseline. This pattern is not seen to the same extent in mild cognitive impairment (MCI) or AD. CSF Aβ42 in MCI or AD shows relatively small serial declines over 1–2 years, for example. Second, a decrease in CSF Aβ40 is not typical of AD. Nevertheless, the time course of these changes is highly relevant to evaluating the impact of treatment interventions, with the hope that predictions used for brain and CSF analysis in mice could help to guide translation into human studies. The species of tau that are found in mouse CSF and their phosphorylation state will be important to investigate further. Also, the mechanism of tau release in the transgenic mice has not been determined.