This is a very nice paper showing direct conversion of skin fibroblasts to well-differentiated, functional glutamatergic human induced neurons (hIN). Use of this direct differentiation method with fibroblasts from PS1 and PS2 FAD subjects resulted in cells with increased Aβ42 (and aberrant APP intracellular localization), providing a proof of concept that this method can be used to derive cellular models expressing physiologic levels of pathogenic proteins in a neuronal cell context. These may be more useful model systems to study AD than those using undifferentiated cells or overexpressing pathogenetic proteins.

View all comments by I. Paul Shapiro

This paper adds to a growing number of publications using iPSCs to study AD-related cellular phenotypes in vitro (Qiang et al., 2011; Israel et al., 2012; Yagi et al., 2011; Shi et al., 2012). It is reassuring to see so many labs independently finding robust phenotypes in their various cell lines. The fact that these cells converge on similar phenotypes with respect to altered APP processing is interesting, and I think we can now be confident that patient-derived neurons are a good model for AD pathogenesis. The next step is to determine the mechanism(s) by which these observed differences in APP processing are leading to cell death in AD. I hope we'll start to see reports where patient-derived neurons are being used to uncover novel disease mechanisms.

For me, the most interesting aspect of this paper is the differential responsiveness to DHA. Understanding why certain cell lines are responsive to treatments whilst others are not could ultimately have implications in the clinic: The success of a particular treatment could depend on patients being "subtyped" appropriately....  Read more

This paper adds to a growing number of publications using iPSCs to study AD-related cellular phenotypes in vitro (Qiang et al., 2011; Israel et al., 2012; Yagi et al., 2011; Shi et al., 2012). It is reassuring to see so many labs independently finding robust phenotypes in their various cell lines. The fact that these cells converge on similar phenotypes with respect to altered APP processing is interesting, and I think we can now be confident that patient-derived neurons are a good model for AD pathogenesis. The next step is to determine the mechanism(s) by which these observed differences in APP processing are leading to cell death in AD. I hope we'll start to see reports where patient-derived neurons are being used to uncover novel disease mechanisms.

For me, the most interesting aspect of this paper is the differential responsiveness to DHA. Understanding why certain cell lines are responsive to treatments whilst others are not could ultimately have implications in the clinic: The success of a particular treatment could depend on patients being "subtyped" appropriately. However, given that this study only examines cells from two familial patients and two sporadic patients, it is difficult to draw any firm conclusions in that respect without expanding this study to include more patients.

References:
Qiang L, Fujita R, Yamashita T, Angulo S, Rhinn H, Rhee D, Doege C, Chau L, Aubry L, Vanti WB, Moreno H, Abeliovich A. Directed conversion of Alzheimer's disease patient skin fibroblasts into functional neurons. Cell. 2011 Aug 5;146(3):359-71. Abstract

Israel MA, Yuan SH, Bardy C, Reyna SM, Mu Y, Herrera C, Hefferan MP, Van Gorp S, Nazor KL, Boscolo FS, Carson CT, Laurent LC, Marsala M, Gage FH, Remes AM, Koo EH, Goldstein LS. Probing sporadic and familial Alzheimer's disease using induced pluripotent stem cells. Nature. 2012 Feb 9;482(7384):216-20. Abstract

Yagi T, Ito D, Okada Y, Akamatsu W, Nihei Y, Yoshizaki T, Yamanaka S, Okano H, Suzuki N. Modeling familial Alzheimer's disease with induced pluripotent stem cells. Hum Mol Genet. 2011 Dec 1;20(23):4530-9. Abstract

Shi Y, Kirwan P, Smith J, Maclean G, Orkin SH, Livesey FJ. A human stem cell model of early Alzheimer's disease pathology in Down syndrome. Sci Transl Med. 2012 Mar 7;4(124):124ra29. Abstract

View all comments by Selina Wray