Massone S, Vassallo I, Castelnuovo M, Fiorino G, Gatta E, Robello M, Borghi R, Tabaton M, Russo C, Dieci G, Cancedda R, Pagano A. RNA polymerase III drives alternative splicing of the potassium channel-interacting protein contributing to brain complexity and neurodegeneration. J Cell Biol. 2011 May 30;193(5):851-66. PubMed.
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UCLA/VA
This paper by Massone and colleagues is intriguing in that they report that IL1-α elevates 38A RNA in a cyclo-oxygenase (COX) inhibitor-sensitive manner, and that AD brain has markedly elevated 38A RNA consistent with an inflammation-driven increase. They find that 38A modulates KCNIP4 splicing to yield more variant IV and less variant I, which the authors also observe in AD brain. Given functional differences in the variants, the alternative splicing reported in AD brain is a novel and interesting result. In-vitro data in neuronal cell lines support a possible impact on A-type potassium currents and perturbed LTP, but this does not seem to have been demonstrated in vivo or in real neurons. Previous work on overexpression of variant 1 KCNIP4 did not show an impact on γ-secretase, so these data are novel. The in-vitro data argue for a KCNIP4 regulation of PS2, but not PS1, leading to a γ-secretase modulation with a shift toward increased Aβ42. I am not a presenilin expert, so it is difficult for me to assess the import of a selective effect on PS2. PS1 has appeared the more critical modulator of Aβ42 production, but given that PS2 mutations can cause AD, I think the new work in this paper will be important to repeat and perhaps build on.
If this study is confirmed, and it is true that this provides a new mechanism for inflammation to increase Aβ42 production and for COX inhibitors to modulate γ-secretase, then these results would extend the rationale for using an anti-inflammatory approach very early in the disease to reduce the buildup of Aβ pathology.
It has been clear for many years that COX inhibitors are not very helpful with established AD and show a lagging protective effect in the epidemiology requiring intervention two or more years prior to AD to show protection. Recent trial results suggest that γ-secretase inhibition in mild to moderate AD may also be unable to provide protection. This raises the question of whether other anti-Aβ strategies will show similar lagging effects, as the non-steroidal anti-inflammatory drug epidemiology suggests for COX inhibitors.