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13 November 2001. 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.
Reference:Andorfer C et al. Characterization of a mouse line that expresses only the
human isoforms of tau. Soc Neuroscience.
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