The AD brain contains innumerable plaques, tangles, neuronal loss and gliosis. The idea that neuronal loss and synaptic loss are associated with impaired neural system function seems straightforward. Clinical-pathological correlation data support the idea that these lesions, as well as neurofibrillary tangle formation, correlate relatively well with dementia severity or duration (Arriagada et al. 1992a,b; Gomez-Isla et al. 1997; Ingelsson et al. 2004; Masliah et al. 1994; Terry et al. 1991). Indeed, neurofibrillary tangles and neuronal loss parallel one another and occur predominantly in parts of the brain that appear to be most affected clinically, such as the medial temporal lobe memory-related neural systems.
While neurofibrillary tangles and neuronal loss affect the same neuronal populations to a great extent, the role of neurofibrillary tangles in neuronal death and dysfunction has remained in doubt. Recent data from a novel transgenic model that overexpresses the P301L tau mutation suggest that the link between neurofibrillary lesions and neuronal death is not as strong as had been supposed (Santacruz et al. 2005; Spires and Hyman 2005). The transgene is expressed on a promoter that can
1 Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, 114 16th Street, Charlestown, Ma 02129 USA
be turned off by oral administration of doxycycline. Innumerable neurofibrillary tangles occur and neuronal loss is widespread. However, when the transgene is turned off, neuronal loss halts but tangles remain. Surprisingly, the animals' performance on memory tests improves in this circumstance, despite the continued presence of tangles. Moreover, stereological assessments suggest that some neuronal populations are lost without developing tangles, whereas others form tangles readily but neuronal loss does not occur. Thus a dissociation between tangle formation and neuronal loss is apparent, confirming earlier observations in patients with AD (Gomez-Isla et al. 1997) of a discrepancy between tangles and neuronal loss. From a therapeutics perspective, this is an important result - blocking neuronal loss remains a vital goal, although neuroprotective strategies lag behind anti-Aß and anti-tangle approaches.
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