NEWS AND VIEWS
Untangling memory deficits Karen Duff & Emmanuel Planel
Snarls of the protein tau accumulate in the brain of individuals with Alzheimer disease and many other degenerative diseases. But what exactly these neurofibrillary tangles, clumped inside of neurons, actually have to do with disease has been difficult to tease out—do they cause degeneration and memory impairment, or perhaps even protect against it? Is another form of tau—not bound up in tangles—the toxic agent? In a recent issue of Science, SantaCruz et al.1 approach the problem with mice using a familiar, but effective approach—a transgene system that suppresses expression of the gene of interest at will, in this case a gene encoding a mutant, disease-associated form of tau. The authors find that after a certain age, tangles continue to accumulate even if tau gene expression is suppressed. What’s more, despite the continued accumulation of tangles, suppressing the gene can impede neurodegeneration and mental decline. The results dovetail with emerging findings on other types of disease-related inclusions, and they hint that therapeutic approaches aimed at reducing the levels of abnormal tau might work. Tauopathies include dementias such as Alzheimer and Pick disease, as well as conditions that, at least initially, are movement disorders, such as progressive supranuclear palsy. In 1998, researchers identified tau mutations that cause a group of familial tauopathies, fronto-temporal dementia and Parkinsonism linked to chromosome 17 (FTDP-17)2, showing beyond any doubt that tau dysfunction can cause neurodegeneration, and renewing interest in the role of tau in other ‘sporadic’ tauopathies including Alzheimer disease. Tau normally binds to, and stabilizes, neuronal microtubules. The binding of tau to microtubules appears to be regulated by phosphorylation, which releases tau from microtubules, decreasing stability but The authors are at the Nathan Kline Institute New York University, School of Medicine, Center for Dementia Research, Orangeburg, New York 10962, USA. e-mail:
[email protected]
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Microtubulebound tau
Unbound phosphorylated tau species
Hyperphosphorylation
Phosphorylated tau aggregation intermediates
Reversible neuronal dysfunction
Neurodegeneration
Stable hyperphosphorylated tau filaments (64 kDa)
Functional deficits
Jason Eriksen
© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
The buildup of protein aggregates consisting of proteins such as tau, huntingtin and amyloid-β occurs in a range of degenerative disorders. Recent studies have begun to shed light on the relative contribution of aggregates versus other, intermediate forms of the protein to disease. The most recent entry in the field examines the protein tau.
Figure 1 Tau and memory. The main function of tau is to bind and stabilize microtubules. Neurofibrillary tangles are thought to develop when an unknown trigger leads to the dissociation of tau from microtubules. This correlates with the accumulation of abnormally phosphorylated tau in the cytoplasm, conformational change and aggregation of insoluble tau into filaments. Santa Cruz et al. have shown that hyperphosphorylated (64 kDa) tau accumulates as tangles even when tau levels are reduced by transgene suppression, possibly because tangles act as a sink for tau intermediates that are predicted to have formed as part of the pathogenic process. Importantly, tangle formation is not associated directly with cognitive decline, which suggests that tau intermediates are the neurotoxic species. Tau intermediates have not yet been identified, but similar intermediates composed of other proteins such as huntingtin or amyloid-β protein have been suggested to be neurotoxic elements in other diseases.
increasing the dynamic nature of the microtubule network. In the disease state, tau becomes hyperphosphorylated at many serine-threonine sites throughout the protein, and it aggregates into insoluble filaments3. Although the linear order of these events is unclear, the formation of tangles is associated with dying back of the neuronal processes and, eventually, with death of the cell. In addition to the question of how tau dysfunction results in neurodegeneration, the relationship between neuronal dysfunction, structural degeneration and clinical progression is uncertain in each of the tauopathies.
SantaCruz et al. developed a transgenic mouse model of tauopathy that makes use of the tet-off regulated promoter system. Their system enables the FTDP-linked mutant (P301L) tau transgene to be suppressed simply by feeding the mice the tetracycline derivative doxycycline. They found that high forebrain levels of transgene expression—13-fold higher than endogenous mouse tau levels—resulted in neurofibrillary tangle formation by 4.5 months, along with the appearance of hyperphosphorylated, insoluble tau. This insoluble, 64 kDa form of tau comigrates with
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© 2005 Nature Publishing Group http://www.nature.com/naturemedicine
NEWS AND VIEWS similar species extracted from the brains of individuals with Alzheimer disease and other tauopathies. At about the same age, the authors observed memory deficits in the mice; by 5.5 months neuronal loss occurred in the hippocampus and by 10.5 months gross brain atrophy was obvious. Although the phenotype in this mouse is impressive, the real significance of the study lies in the experiments turning off the gene. The authors treated mice of various ages with doxycycline, and achieved 85% suppression of transgene expression. Whereas suppressing the transgene at 2.5 months essentially halted further development of pathology, suppression at 4 months or older led to something unexpected: neurofibrillary tangles continued to accumulate despite the reduced levels of tau. The correlation between tangle perpetuation and appearance of the 64 kDa hyperphosphorylated insoluble tau species suggests that the 64 kDa form is a stable conformation favoring ongoing aggregation even at low levels of tau. This pattern of aggregation is reminiscent of amyloidogenic proteins that after an initial nucleation event require lower levels of the monomer to support continued aggregation. The major surprise occurred when the researchers examined cognitive decline. At each timepoint examined in mice older than 4 months, transgene suppression halted neuronal loss, despite the continued increase in tangle number. Moreover, memory function fully recovered in mice from 2.5 to 4 months of age after transgene suppression. Amazingly, mice treated with doxycycline at 5.5 months partially recovered memory function by 7 and 9 months of age, even when hippocampal neuronal loss had already occurred. If future studies bear them out, these findings have profound implications. They indicate that—at least in this mouse model—tangle formation does not lead to neuronal loss and neurodegeneration, and cannot account directly for memory loss. These observations parallel recent findings in another model that more closely recapitulates Alzheimer disease tauopathy4, in which neuronal loss also exceeds the number of tangles. Furthermore, in a mouse study in which insoluble phosphorylated tau species were reduced after administration of a kinase inhibitor, degeneration was suppressed but neuropathology markers were not markedly altered5. It is not clear whether the neurofibrillary tangles in these mouse models are merely markers of the disease process, or whether they actually protect against neurodegeneration by sequestering toxic soluble tau species
into a less harmful state. A study showing that the formation of inclusion bodies could reduce the toxic effects of mutant huntingtin6 suggests that the latter is certainly possible. The work of SantaCruz et al. also suggests that the memory deficits in the model can be explained, at least partially, by reversible neuronal dysfunction rather than irreversible structural degradation, given that memory could be recovered even after considerable hippocampal loss. Alternatively, neuronal plasticity or even neurogenesis may account for part of the recovery. The functional recovery is also reminiscent of results from models for related neurodegenerative diseases, Creutzfeldt-Jakob disease and Alzheimer disease. In a CreutzfeldtJakob disease model, inducible knockout of neuronal prion protein prevents clinical manifestations of scrapie infection even though insoluble prion protein aggregates continue to accumulate7. In plaque-forming Alzheimer disease models, functional recovery follows immunotherapy with antibodies to the amyloid-β protein, but this is dissociated from changes in the amount of amyloid plaque protein8,9. These and other studies seem to point to a consistent conclusion—that the insoluble protein aggregates that often define neurodegenerative diseases neuropathologically do not directly cause neurodegeneration and the functional deficits observed in mouse models. Despite these new insights, many questions remain. If the neurofibrillary tangles are not the toxic species, then what is? One possibility (Fig. 1)—similar to that proposed for huntingtin degeneration6—is that diffuse, hyperphosphorylated, aggregated tau intermediates initially cause neuronal dysfunction and eventually structural neurodegeneration. The reduction in the generation of these species after transgene suppression allowed functional recovery, but tangle formation continued because the aggregates act as a sink, requiring lower levels of the intermediates to support continued filament formation. A second possibility is that abnormally phosphorylated tau could be the neurotoxic intermediate. This notion is supported by converging evidence that hyperphosphorylated tau can cause neurodegeneration without forming large aggregates10, but as yet the role of hyperphosphorylation and conformational change in degeneration and memory impairment, and even the sequence of events, remain to be determined. Finally, the most crucial unresolved issue is whether the recovery of memory in this
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mouse model will predict similar functional recovery in individuals with tauopathies. Observations from individuals with FTDP-17 with P301L mutations support the existence of neurotoxic tau intermediates in humans, as these individuals can have extensive neurodegeneration with comparatively few tangles11. However, in predicting whether these results have implications for all tauopathies—whether associated with mutant or wild-type tau accumulation—the differences between FTDP-17 and Alzheimer disease should be taken into acccount10. For example, in Alzheimer disease, but not in individuals with FTDP-17 with P301L mutations, both neuronal loss and neurofibrillary tangle number increase in parallel with the duration and severity of the disease, with the neuronal loss exceeding but correlating with the number of neurofibrillary tangles12. Thus, although data from individuals with FTDP-17 support the disconnect between neurofibrillary tangle formation and memory dysfunction, it is difficult to dismiss the role of tangles in memory loss in individuals with Alzheimer disease. Toxic intermediates are likely to also occur in Alzheimer disease, however, as a mouse overexpressing wild-type tau develops Alzheimer disease–type tangles, but many severely degenerate neurons have sparse neurofibrillary pathology4. Given that tau intermediates and tangles are likely to colocalize extensively, separating out the contribution of each to degeneration and cognitive decline is difficult—hence the significance of the suppression studies described by SantaCruz et al. Whatever the cause, therapeutic intervention for the tauopathies will probably need to be started early in the disease process to halt or reverse cognitive decline, making the development of improved diagnostic methods and welltolerated drugs a necessity. 1. SantaCruz, K. et al. Science 309, 476–481 (2005). 2. Hutton, M. et al. Nature 393, 702–705 (1998). 3. Alonso, A.C., Zaidi, T., Novak, M., Grundke-Iqbal, I. & Iqbal, K. Proc. Natl. Acad. Sci. USA 98, 6923– 6928 (2001). 4. Andorfer, C. et al. J. Neurosci. 25, 5446–5454 (2005). 5. Noble, W. et al. Proc. Natl. Acad. Sci. USA 102, 6990–6995 (2005). 6. Arrasate, M., Mitra, S., Schweitzer, E.S., Segal, M.R. & Finkbeiner, S. Nature 431, 805–810 (2004). 7. Mallucci, G. et al. Science 302, 871–874 (2003). 8. Dodart, J.C. et al. Nat. Neurosci. 5, 452–457 (2002). 9. Kotilinek, L.A. et al. J. Neurosci. 22, 6331–6335 (2002). 10. Brandt, R., Hundelt, M. & Shahani, N. Biochim. Biophys. Acta 1739, 331–354 (2005). 11. Bird, T.D. et al. Brain 122, 741–756 (1999). 12. Gomez-Isla, T. et al. Ann. Neurol. 41, 17–24 (1997).
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