This is a remarkable study illustrating the relationship of human tau expression, neuronal loss, and tau filaments. The dissociation of tau filaments and cell death provides provocative evidence against the contributing role of tau filaments in cell death. On the other hand, the researchers' findings also hint at an unexpected role of human tau in inducing cell cycle re-entry and DNA synthesis. This is a highly novel mechanism for tau-mediated neurodegeneration.

View all comments by Li-Huei Tsai

This is a most interesting and provocative study. It adds yet another wrinkle to the AD pathology cascade and suggests that cell cycle re-expression may be a major factor in the eventual cell death seen in AD. Data generated from our laboratory showing neurotrophin receptor dysfunction in MCI and early AD, in combination with findings from our collaborative studies with Karl Herrup and colleagues showing cell cycle markers in basal forebrain neurons during the prodromal stage of AD, further indicates that multiple processes underlie the ultimate demise of neurons in AD. Studies demonstrating the relationship of abnormal or normal tau with the onset of cell cycle markers during the progression of AD are in progress.

View all comments by Elliott Mufson

The Wheel of Death: Neuronal Cell Cycle and Alzheimer Disease
There are multiple unanswered questions related to the pathogenesis of Alzheimer disease (AD). However, a major step forward in answering at least three important aspects was recently provided by Peter Davies and colleagues looking at aged mice expressing non-mutant human tau (Andorfer et al., 2005). These mice elicit neurodegeneration, allowing temporal and mechanistic studies. In this paper, there are three major observations. First, neurodegeneration occurs independently of neurofibrillary tangle formation. This is an intriguing observation and further highlights the disconnect between pathology and pathogenesis seen in Alzheimer disease (Lee et al., 2005). Second, neurodegeneration is associated with the re-expression of cell cycle proteins. Aberrant cell cycle re-entry is thought by many to be involved in the pathogenesis of AD; however, whether this is necessary and/or sufficient for disease has proved somewhat enigmatic. That the animal shows a similar phenotype sets the stage to next determine...  Read more

The Wheel of Death: Neuronal Cell Cycle and Alzheimer Disease
There are multiple unanswered questions related to the pathogenesis of Alzheimer disease (AD). However, a major step forward in answering at least three important aspects was recently provided by Peter Davies and colleagues looking at aged mice expressing non-mutant human tau (Andorfer et al., 2005). These mice elicit neurodegeneration, allowing temporal and mechanistic studies. In this paper, there are three major observations. First, neurodegeneration occurs independently of neurofibrillary tangle formation. This is an intriguing observation and further highlights the disconnect between pathology and pathogenesis seen in Alzheimer disease (Lee et al., 2005). Second, neurodegeneration is associated with the re-expression of cell cycle proteins. Aberrant cell cycle re-entry is thought by many to be involved in the pathogenesis of AD; however, whether this is necessary and/or sufficient for disease has proved somewhat enigmatic. That the animal shows a similar phenotype sets the stage to next determine whether this mechanism is truly a wheel of death by therapeutic interventions targeting cell cycle re-entry (Webber et al., 2005). Third, despite showing evidence of DNA fragmentation, there is little or no evidence of caspase activation in this model. Again, this parallels the confusion of cell death mechanisms in AD (Raina et al., 2001). As such, the model faithfully replicates several of the big questions in AD (i.e., are cell cycle and/or neurofibrillary tangles involved in cell death and do cells die by apoptosis?). Future studies will hopefully answer these and provide insights into AD pathogenesis.

References:
Andorfer C, Acker CM, Kress Y, Hof PR, Duff K, Davies P. Cell-cycle reentry and cell death in transgenic mice expressing nonmutant human tau isoforms. J Neurosci. 2005 Jun 1;25(22):5446-54. Abstract

Lee HG, Perry G, Moreira PI, Garrett MR, Liu Q, Zhu X, Takeda A, Nunomura A, Smith MA. Tau phosphorylation in Alzheimer's disease: pathogen or protector? Trends Mol Med. 2005 Apr;11(4):164-9. Abstract

Raina AK, Hochman A, Zhu X, Rottkamp CA, Nunomura A, Siedlak SL, Boux H, Castellani RJ, Perry G, Smith MA. Abortive apoptosis in Alzheimer's disease. Acta Neuropathol (Berl). 2001 Apr;101(4):305-10. Abstract

Webber KM, Raina AK, Marlatt MW, Zhu X, Prat MI, Morelli L, Casadesus G, Perry G, Smith MA. The cell cycle in Alzheimer disease: A unique target for neuropharmacology. Mech Ageing Dev. 2005 Jun 1; [Epub ahead of print]

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