15 July 2005. In Alzheimer and some other neurodegenerative diseases, the microtubule-associated protein tau weaves a web of neurofibrillary tangles (NFTs) that might be toxic to neurons. But alternative interpretations suggest that NFTs, by sequestering tau, are in fact neuroprotective, or, at the very worst, they are the product of an incidental side reaction. To untangle this sticky problem, Karen Hsiao Ashe of the University of Minnesota Medical School in Minneapolis and collaborators from Massachusetts General Hospital and the Mayo Clinic in Jacksonville, Florida, have generated a new tau transgenic mouse in which the overexpression of mutant human tau can be regulated by tetracycline. In this model, turning off tau expression after deposits have formed halts neuron loss and reverses memory defects. But surprisingly, neurofibrillary tangles continue to accumulate, suggesting that they are not responsible for neurodegeneration.
The data, reported in today’s Science, mesh with a recent report from Peter Davies and Karen Duff (Andorfer et al., 2005), which suggested that neuronal loss induced by human tau expression in mice does not track with neurofibrillary tangle formation. Together, these results should turn attention away from tangles to a search for other mechanisms of tau-induced neuronal death. And the new observation that some tau-related cognitive deficits are reversible in mice raises the hope that early intervention to blunt tau’s damage in humans could yield benefits in AD and other tauopathies.
The new tau mice, the product of a three-way collaboration between co-first authors Karen SantaCruz, Jada Lewis, and Tara Spires, manifested tau toxicity early in life as a result of overexpression of the P301L human tau mutant in the forebrain. By the time they were 4 months old, the mice had visible tau deposits. At 5.5 months, the animals showed a decrease in brain weight and in the number of hippocampal neurons. Pathology progressed by 10 months to include gross atrophy of the forebrain, accompanied by accumulation of NFTs containing hyperphosphorylated tau. Behaviorally, by 2.5 months the mice had impaired performance in the Morris water maze, while by 4 months old they were swimming randomly, a sign of severe spatial memory deficits.
After characterizing the “tau-on” mice, the investigators switched tau off by administering doxycycline, which represses the tetracycline promoter, and watched what happened to the tangles, neurons, and behavioral and cognitive performance. In mice fed doxycycline, tau mRNA decreased by 85 percent and soluble tau protein levels diminished by three-quarters. When tau was switched off at 2.5 months, the progression of tangle formation and neuronal loss was halted. But if repression of human tau was delayed until 4 months, NFTs continued to increase. Around this age, a 64-kd insoluble tau species first appeared, which the authors speculate could act as a sink for the residual mutant tau in these older mice.
But despite the continued accumulation of tangles, turning off tau in these older mice did protect them against neuron loss and cognitive deficits. When tau was suppressed continuously from 5.5 months to 9.5 months, the mice did not lose brain weight, for example. Turning off tau for short periods between 2.5 and 8.5 months also stabilized the number of hippocampal neurons, suggesting that NFTs “do not invariably cause neuron death,” write the authors.
In the memory task, early cognitive deficits observed in young (2.5-month-old) mice in the Morris water maze actually improved when tau was turned off, suggesting that the processes leading to early memory defects might be reversible. Tau suppression at later times (5.5 months) elicited an improvement of memory function, but not to levels seen in young mice. “That memory function improved in > 4-month-old mice fed doxycycline despite ongoing accumulation of NFTs clearly implies dissociation between the processes that lead to memory loss and those that cause NFTs, and that the NFTs remaining after tau suppression are not sufficient to disrupt cognitive function,” the authors conclude.—Pat McCaffrey.
SantaCruz K, Lewis J, Spires T, Paulson J, Kotilinek L, Ingelsson M, Guimaraes A DeTure M, Ramsden, M, McGowan E, Forster C, Yue M, Orne J, Janus C, Mariash A, Kuskowski M, Hyman B, Hutton M, Ashe KH. Tau Suppression in a Neurodegenerative Mouse Model Improves Memory Function. Science. 15 July 2005; 309:476-4481. Abstract