Neurofibrillary tangles (NFTs) are the most common intraneuronal inclusion in the brains of patients with neurodegenerative diseases and have been implicated in mediating neuronal death and cognitive deficits. Here, we found that mice expressing a repressible human tau variant developed progressive age-related NFTs, neuronal loss, and behavioral impairments. After the suppression of transgenic tau, memory function recovered, and neuron numbers stabilized, but to our surprise, NFTs continued to accumulate. Thus, NFTs are not sufficient to cause cognitive decline or neuronal death in this model of tauopathy.

Transgenic mice expressing mutant amyloid precursor proteins (APPs) have provided important new information about the pathogenesis of Alzheimer's disease (AD) histopathology. However, the molecular basis of memory loss in these mice is poorly understood. One of the major impediments has been the difficulty of distinguishing between age-dependent and ageindependent behavioral changes. To address this issue we studied in parallel two lines of APP transgenic mice expressing comparable levels of mutant and wild-type human APP. This enabled us to identify age-independent behavioral deficits that were not specifically related to mutant APP expression. When mice with age-independent deficits were eliminated, we detected memory loss in transgenic mice expressing mutant APP (Tg2576 mice) starting at ϳ6 months, which coincided with the appearance of detergent-insoluble A␤ aggregates (A␤ insol ). Genetically accelerating the formation of A␤ insol resulted in an earlier onset of memory decline. A facile interpretation of these results, namely that memory loss and A␤ insol were closely connected, was rejected when we extended our analysis to include older mice. No obvious correspondence between memory and A␤ insol was apparent in a combined group of old and young mice unless the mice were stratified by age, whereupon inverse correlations between memory and A␤ insol became evident. These results suggested that A␤ insol is a surrogate marker for small assemblies of A␤ that disrupt cognition and occur as intermediates during A␤ insol formation, and they are the first descriptive in vivo data supporting their role in impairing memory. These studies also provide a methodological framework within which to investigate these A␤ assemblies in vivo.

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