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.
In agreement with Christian Haass, I recommend prudence in linking, unequivocally, the forced expression of 38A ncRNA to the pathological manifestations of AD. We must be cautious in ascribing to its over-synthesis a causative mechanism of AD onset. In this regard, our work reports that “at present it is not clear if 38A is essential for AD onset or rather it is part of a pathologic condition of the brain that occurs in numerous neurodegenerative disorders,” and that our results “suggest its contribution to the disease in association with other possible elements.”
Nonetheless, the fact that “this model provides a novel way to investigate neurodegeneration and brain function based on an alternative cascade of reactions unexpectedly controlled by an ncRNA transcribed by pol III” is relevant, and might open the way to novel explorations of brain pathology. In this context, as suggested by Greg Cole, the best way to know the involvement of 38A ncRNA in AD is to evaluate the consequences of its synthesis in mouse hippocampal and cortical neurons, a work currently in progress. Different lines of transgenic mice stably overexpressing 38A ncRNA have been generated and, hopefully, will provide novel information about 38A's biological role. If a causative action of 38A ncRNA overexpression on AD onset can be clearly demonstrated, this mouse model will also provide a suitable way to test the role of inflammation (and of anti-inflammatory drugs) on this small ncRNA, and on the possible pathological consequences of its synthesis.
University of Texas at Austin
Although inflammation appears to be a contributor to the pathology of AD, it is unlikely to be a causal event of this dementia, as I have recently reviewed in a paper that analyzes current AD hypotheses. A considerable number of hypothetical proposals suggesting the cause of AD have been published in the last decades, and none so far has reached a consensus of agreement by experts in the field. Hence, it is fundamental that any likely proposed cause of AD needs to satisfy strict criteria derived by evidence-based medicine from randomized controlled trials.
AD progress will not move forward until we set in motion efficient therapeutic initiatives designed to prevent, reverse, or slow down the likely cause of this disorder, not the imagined or convenient cause that is good for grant-getting but is unsupported by the available clinical evidence.
References:
de la Torre JC. Three postulates to help identify the cause of Alzheimer’s disease. J Alzheimers Dis. 2011;24(4):657-68. PubMed.
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