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Moore S, Evans LD, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ. APP metabolism regulates tau proteostasis in human cerebral cortex neurons. Cell Rep. 2015 May 5;11(5):689-96. Epub 2015 Apr 23 PubMed.
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University Clinic Cologne
In this study by Moore et al., the authors chose a very interesting approach to replicate familial AD (fAD) pathology in vitro. They converted fibroblasts of patients with different fAD mutations into induced pluripotent stem cells (iPSCs), which they then differentiated into excitatory forebrain neurons. As expected, these human neurons then showed different processing of APP, resulting in different levels and ratios of Aβ peptides, depending on the mutation. These results correlate nicely with previously published results on APP processing from various labs (e.g. DeStrooper, Haass, Sisodia labs and others), and it is quite a relief that human neurons do show roughly the same behavior as the cell lines and transgenic mouse models used in other studies.
Interestingly, two of the fAD mutations tested (a duplication of APP and the V171I mutation of APP, both of which change total amounts of APP expression) resulted in higher levels of tau (approximately two- to fourfold) in these iPSC-derived human neurons. Phospho-tau, however, remained unchanged, when compared to total tau expression.
This is certainly an interesting point that would require replication and a suitable sample size. The direct implication of this result, however, is unclear, because i) the increase in total tau is within the range produced by other mutations and the controls, ii) intraindividual controls are missing and iii) no other cellular parameters have been tested, thereby it is difficult to judge the general state of the cells. E.g., increased axonal growth due to higher trophic levels of a trophic APP fragment would also result in higher levels of tau.
The authors also tested the effects of β- and γ-secretase inhibitors and modulators on tau levels, and found that these can change not just the processing of APP, but also the total tau levels, at least in the case of most samples analyzed. These experiments are unfortunately difficult to judge. These cells are obviously still growing/developing and it is unclear how this is affected by the drug treatments. The drug dosing is also rather rough, with 1-10µM applied every two days for a period of up to 30 days, which might result in the accumulation of the drug and severe side effects. Finally, phospho-tau levels only increased or decreased in parallel with total tau. Thus, even if one considers phospho-tau pathological, there seems to be no tau pathology here.
Tau phosphorylation and upregulation is a very normal process during development or axon extension, and of course tau is not only a marker for AD-like pathology, but also a neuronal or axonal marker, and thereby also a marker for proper axonal growth (see, e.g., Zempel and Mandelkow, 2014, for discussion). As these parameters (as well as general health markers, etc.) are not part of this study it is difficult to draw conclusions for therapeutic interventions. However, if these findings can be replicated and γ-secretase modulators are capable not only of decreasing pathogenic Aβ peptides, but also reducing tau levels without affecting axonal growth or general neuronal health, then one could tackle the two pathological drivers of AD at the same time, at least for some mutations. Whether this would be beneficial for all mutations of fAD or for other tauopathies is uncertain, therefore there is still a great need to develop tau-based therapeutics. However, this paper describes an encouraging novel approach that will surely lead to a better understanding of the roles of Aβ and tau in neurons.
Zempel H, Mandelkow E. Lost after translation: missorting of Tau protein and consequences for Alzheimer disease. Trends Neurosci. 2014 Dec;37(12):721-32. Epub 2014 Sep 12 PubMed.
The results reported are interesting and certainly the use of iPSCs has a lot of promise in uncovering mechanisms. However, I think the findings reported are difficult to interpret in regard to any relationship they do or don’t have with fAD. A technical issue is that the authors never used technology to convert the mutations in the iPSCs back to normal. This is a much better control than iPSCs from separate individuals without the mutations.
In terms of the scientific findings, the changes in tau reported with one APP mutation and in the APP duplication are not the kind of pathological tau seen in AD or in tauopathies. For example, there are no insoluble tau or tau fibrils demonstrated. Also, there is no evidence of Aβ aggregation or deposition in this culture system.
Finally, PS1 mutations end up causing clear-cut tauopathy in human brain (after Aβ deposition), yet in this system, no tau “abnormality” is seen in the PS1 iPSC-derived neurons. One would think that the mechanisms leading to tauopathy would more likely be the same in different APP or PS mutations.
Thus, while the changes in APP fragments seen in iPS neurons derived from APP duplication and other APP mutations are interesting, whether the changes in tau levels observed in the iPSC-derived neurons is related to the changes in tau seen in AD, in which there is hyperphosphorylated, aggregated tau with PHFs, is not clear.
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