Bali J, Gheinani AH, Zurbriggen S, Rajendran L.
Role of genes linked to sporadic Alzheimer's disease risk in the production of β-amyloid peptides.
Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15307-11.
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This study by Bali et al. provides compelling evidence that downregulation of the late-onset AD (LOAD) risk genes in cell cultures does not alter Aβ generation in a pathologically meaningful way, and suggests that increased Aβ42 levels or Aβ42/40 ratio may not be the driving force of disease pathogenesis in the majority of AD cases (i.e., LOAD cases). Limitations of their experimental approach notwithstanding, it is difficult to argue against the overarching implications of their findings.
The limitations pointed out by others are valid but irrelevant, or not significant to the authors’ conclusions. RNAi methodology can have off-target effects, but it is almost impossible that reagents used to silent all 24 genes would have similar off-target effects. True, some of the AD risk genes may act by gain of function, but to imagine that all 24 genes do so is highly improbable. To affect Aβ clearance, the AD risk genes must fall in one of three categories: proteases that degrade Aβ, regulators of macrophage-mediated Aβ uptake, or be localized to the blood-brain barrier and mediate Aβ export. Again, it is difficult to see how all 24 AD risk genes examined here fall into one of the three categories.
Finally, the argument that the use of tissue culture cells overexpressing APPswe mutation somehow invalidates their conclusions (since the vast majority of LOAD cases have wild-type APP) would also invalidate a very large body of published work.
Thus, if one accepts their conclusion that the 24 AD risk genes studied here do not alter Aβ production in a meaningful way and, as argued above, are unlikely to regulate Aβ clearance, then one must entertain the possibility that some of the AD risk genes act by a mechanism that does not involve Aβ metabolism. Overall, these findings are consistent with the view that AD pathogenesis is a multifactorial process and that not all cases of AD may be explained by the amyloid hypothesis (Pimplikar et al., 2010). The preliminary reports that nasal insulin therapy or intravenous immunoglobulin administration seems to confer beneficial effects in clinical studies supports such a view.
Pimplikar SW, Nixon RA, Robakis NK, Shen J, Tsai LH.
Amyloid-independent mechanisms in Alzheimer's disease pathogenesis.
J Neurosci. 2010 Nov 10;30(45):14946-54.