. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012 Jan 25;482(7384):216-20. PubMed.


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  1. The use of human induced pluripotent stem (iPS) and induced neuronal (iN) cells is clearly a major step forward compared to standard clonal cell lines, and also to our own mainstay system, cultured primary AD transgenic neurons. However, the results with induced cells are not yet all that easy to fully interpret. Findings of an elevated Aβ42/40 ratio (Qiang et al., 2011; Yagi et al., 2011) fit well with what is known from prior work on familial AD (FAD) mutations. The enlarged early endosomes seen both by Qiang et al., and now Israel et al., also fit well with pioneering work by Ralph Nixon and Ann Cataldo. Yet it is still unclear if these genetically engineered cells are equivalent to primary human neurons. Israel and colleagues’ evidence that tau is altered by C-terminal fragments (CTFs) of amyloid precursor protein (APP) rather than Aβ builds on a growing literature of Aβ-independent effects due to FAD mutations (here, APP duplications). However, these observations are based on treatment with γ-secretase inhibitors. which can be tricky because of potential effects on iPS cell differentiation, toxicity, etc. In addition, a considerable number of divergent data point to Aβ rather than CTFs as being critical.

    In our experience, limited (overnight) γ-secretase inhibition did prevent both alterations in synapses (Almeida et al., 2005; Tampellini et al., 2009) and endocytosis (Almeida et al., 2006), albeit in mutant APP-overexpressing transgenic neurons. In contrast, longer treatments (or higher concentrations) with γ-secretase inhibitor were not protective. Based on work in primary transgenic neurons, synapsin 1 would also not be the optimal marker to use for identifying presynaptic changes, which Israel et al. found to be unchanged in their AD iPS cells. It will be important to obtain more data with these exciting new model systems as noted by Abeliovich in the ARF news story.


    . Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell. 2011 Aug 5;146(3):359-71. PubMed. RETRACTED

    . Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet. 2011 Dec 1;20(23):4530-9. PubMed.

    . Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. PubMed.

    . Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. PubMed.

    . Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci. 2006 Apr 19;26(16):4277-88. PubMed.

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