For years, scientists have tried to create transgenic mice that form neurofibrillary tangles, one of the two pathological hallmarks of Alzheimer's disease. All attempts failed until last year, when researchers led by Jada Lewis and Mike Hutton published a report of a transgenic mouse strain that developed intraneuronal deposits resembling tangles (Lewis J et al. 2000). That mouse carries a mutated version of tau that causes the disease frontotemporal dementia with Parkinsonism (FTDP-17); however, no tau mutations are known in Alzheimer's.
Yesterday at the Neuroscience meeting, researchers led by Peter Davies reported that they have succeeded in generating a mouse model that more closely mimics the sort of tau pathology seen in AD. The trick was to remove mouse tau and express human tau only, Davies said.
The mouse model will help researchers interested in tau catch up with their amyloid brethren. Amyloid mice have been available for at least six years, and have enabled investigation of questions ranging from the mechanism of plaque formation to drug testing and the development of experimental immunotherapies.
The human tau-transgenic mice are now up to nine months old. Tau pathology begins at about three months of age and progresses from there to the formation of full-fledged tangles. Previously, the field has debated what qualifies as a tangle in mouse. Davies claims his mice clearly fit the bill.
At nine months, the mice do not show overt neurodegeneration. The neurons that have tangles do look sick but there is no massive cell death, as happens in AD. Like in AD, however, some neurons are full of tangles whereas neighboring neurons are less or not at all affected. The reason why some neurons are more vulnerable than others remains elusive.
Davies said among the questions to be studied now are the mechanism of tangle formation and the testing of drugs against potentially useful targets, such as GSK3, that pharmaceutical companies have developed. Until now, companies lacked a mouse model that could provide a clear readout on how these drugs affect tangle formation.
Mating the human wildtype tau-transgenic mice with APP-transgenic mice is an obvious experiment. Would such mice represent a complete and faithful AD model in that they have both neurofibrillary and amyloid pathology? No, said Davies. He thinks these mice will likely show two parallel, independent pathologies because they are caused by two separate genetic manipulations in the mouse, whereas he believes both pathologies develop in AD as a consequence of a still-unknown trigger.—Gabrielle Strobel
References: Andorfer C et al. Characterization of a mouse line that expresses only the human isoforms of tau. Soc Neuroscience.
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- Lewis J, McGowan E, Rockwood J, Melrose H, Nacharaju P, Van Slegtenhorst M, Gwinn-Hardy K, Paul Murphy M, Baker M, Yu X, Duff K, Hardy J, Corral A, Lin WL, Yen SH, Dickson DW, Davies P, Hutton M. Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein. Nat Genet. 2000 Aug;25(4):402-5. PubMed.