Paper
- Alzforum Recommends
Boekhoorn K, Terwel D, Biemans B, Borghgraef P, Wiegert O, Ramakers GJ, de Vos K, Krugers H, Tomiyama T, Mori H, Joels M, Van Leuven F, Lucassen PJ. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006 Mar 29;26(13):3514-23. PubMed.
Recommends
Please login to recommend the paper.
Comments
In this study, Boekhoorn et al. investigated synaptic plasticity, learning, and memory in young versus aged tauP301L mice. They found that learning in the novel object paradigm was significantly better in young tauP301L mice when compared to a control group. In addition, long-term potentiation, which is commonly viewed as a molecular correlate for learning and memory, was found to be enhanced in tauP301L mutant mice when measured in the perforant path-dentate gyrus pathway of the hippocampus. These findings are very surprising, since the tauP301L mutation is linked to frontotemporal dementia with parkinsonism (FTDP-17) in humans, and tau pathology is one of the hallmarks of the pathogenesis of Alzheimer disease (AD). Consistently inducible overexpression of tauP301L in the forebrain of mice causes severe cognitive deficits in aged mice (Santacruz et al., 2005).
Although the mechanism by which tauP301L causes facilitated memory in young mice is not clear (Boekhoorn et al. ruled out morphological changes or neurogenesis in the hippocampus as underlying mechanisms), these findings are interesting in view of the previously formulated hypothesis that a failure in neuroplasticity may be the common feature in the pathogenesis of sporadic AD (Mesulam, 1999; Arendt, 2004). This hypothesis predicts that tau and APP are plasticity factors that, when deregulated, cause a failure in neuroplasticity which eventually leads to the manifestation of amyloid plaques and neurofibrillary tangles and neuronal loss. That overexpression of a mutant tau initially facilitates learning and synaptic plasticity but eventually contributes to cognitive impairment, and neuronal cell death fits this hypothesis very well. In line with this observation, our laboratory recently demonstrated that expression of p25, the truncated form of the cyclin-dependent kinase 5 (Cdk5) activator p35, initially facilitates synaptic plasticity, learning, and memory in mice (Fischer et al., 2005). Cdk5/p25 has been implicated in the pathogenesis of AD in humans, and consistently we found that chronically elevated p25 levels lead to severe neuronal and synaptic loss accompanied by impaired learning and memory in mice (Fischer et al., 2005). In summary, this data seem to support the idea that the main players implicated in the pathogenesis of sporadic AD might normally function as mediators of neuroplasticity, as long as their activity is tightly controlled. Future research is needed to identify and understand the processes that deregulate tau, Cdk5, and APP signaling and to understand the interaction among these potential plasticity factors. This will not only help to further understand learning and memory but also to identify novel strategies to prevent Alzheimer disease.
References:
Arendt T. Neurodegeneration and plasticity. Int J Dev Neurosci. 2004 Nov;22(7):507-14. PubMed.
Fischer A, Sananbenesi F, Pang PT, Lu B, Tsai LH. Opposing roles of transient and prolonged expression of p25 in synaptic plasticity and hippocampus-dependent memory. Neuron. 2005 Dec 8;48(5):825-38. PubMed.
Mesulam MM. Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 1999 Nov;24(3):521-9. PubMed.
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. 2005 Jul 15;309(5733):476-81. PubMed.
View all comments by Andre FischerThe University of Queensland
This study of a beneficial effect of tau as shown by improved long-term
View all comments by Jürgen Götzpotentiation, in the absence of tau hyperphosphorylation, demonstrates
that tau mutations, such as P301L, are not per se causing cognitive
decline. As this research group has in the past also generated human
wild-type tau transgenic mice without carrying mutations, it would be
an interesting follow-up study to repeat the electrophysiology, Golgi
stainings, and the analysis of neurogenesis with these mice to determine
whether higher wild-type tau levels would lead to even more improvement.
Laboratory for Alzheimer Disease
Boekhoorn and colleagues indicated that their P301L tau transgenic mice showed higher LTP and memory performance when they are young—before NFTs and hyperphosphorylation have occurred yet. But Mandelkow’s group found that tau overexpression inhibits the anterograde transport along microtubules by obstructing kinesin movement; their result was rather opposite.
If P301L mutant tau binds to the microtubule, axonal transport should be inhibited, leading to synaptic dysfunction. However, young Tg mice exhibited “improvement” of synaptic function compare to non-Tg mice. Tau overexpression may, therefore, have two effects. On the one hand, it improves synaptic function in young mice, and on the other, it causes neurodegeneration through hyperphosphorylation and aggregation in cytoplasm of older animals. In the case of human brain, tau never gets overexpressed during the entire lifespan. Tau does accumulate in the case of FTDP-17, where it induces NFTs and neuronal loss without overexpression. Therefore, we need to clarify the effects of tau mutations, rather than overexpression, on neuronal function for understanding the mechanism of neurodegeneration in human tauopathies, including AD. In this sense, by comparing P301L mutant with wild-type tau Tg mice, we may be able to understand what factors play the critical role in neuronal dysfunction in tauopathies.
View all comments by Akihiko TakashimaMake a Comment
To make a comment you must login or register.