Lehmann SM, Krüger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kälin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock D, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S.
An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration.
Nat Neurosci. 2012 May 20;
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This article by Lehmann et al. presents interesting results in mice regarding induction of neuronal death by let-7 miRNA through TLR-7 on neurons. They confirmed the results in Tlr7-/- mice, including the Tlr7-/- mice from fetuses transfected by TLR7. This mode of neuronal death could be implicated in patients with Alzheimer's disease (AD) who suffered brain trauma, which is one of the risk factors of AD. The relevance to patients with sporadic AD is difficult to evaluate at present. Their study included 13 patients with MMSE 18-28 and 11 control subjects, but the incidence of brain trauma and other associated conditions, such as stroke and diabetes, was not listed. The significance of let-7 differences in the CSF was stated as 0.0139, but it does not seem that the data were evaluated by the Levene Test for Equality of Variances. Thus, the results remain an interesting link of let -7 to neurodegeneration in an animal model, but with only weak connection to AD neuropathology and amyloid-β. It would be interesting to evaluate let-7 in the CSF of patients with brain trauma, which could provide much better comparison (acute brain trauma vs. no trauma vs. meningitis, etc.).
There is growing evidence showing that Toll-like receptors (TLRs) play a key role in the pathogenesis of Alzheimer¹s disease (AD): 1) TLRs are upregulated in AD patients and AD animal models; 2) CD14, the co-receptor of TLR4, and TLR2, has been observed to directly interact with aggregated amyloid-β peptide (Aβ) and trigger microglial neurotoxic inflammatory activation; 3) experimental manipulations to activate TLR4 or TLR9, and to inhibit CD14, TLR2, TLR4, or MyD88, a signaling molecule downstream of TLRs, have been shown to change AD-like pathology, for example, neuroinflammation, Aβ load, and neuronal degeneration in amyloid precursor protein (APP) transgenic mice. In these studies, scientists mainly focus on: 1) effects of microglial TLRs, (although the effects of neuronal TLRs cannot be excluded in experiments cross-breeding TLR2- or TLR4-knockout mice and APP transgenic mice); 2) Aβ as the ligand of TLRs, although other ligands, for example, high-mobility group box-1, could also activate TLRs.
This publication in Nature Neuroscience by Lehnardt and her colleagues indicates that TLR7 could be a new innate immune receptor promoting AD pathogenesis. The endogenous ligand for this receptor is a sequence motif (GUUGUGU) contained in microRNAs. Here, microRNAs induce neurodegeneration instead of their conventional role of regulating gene transcription.
However, the most interesting finding in this publication is that activation of neuronal TLR7 directly causes neuronal death, whereas activation of microglial TLR7 triggers an inflammatory response with secondary neurotoxic effects. These findings extend the concept of innate immunity, as neurons also exert innate immune functions, although the immune signaling cascades in neurons could be different in microglia or macrophages. Whether TLR7 really plays an important role in AD pathogenesis still needs further animal experiments, for example, conditionally ablating neuronal TLR7 in AD mouse models. Whether the concentration of extracellular microRNAs is sufficient to activate TLR7 should also be further investigated.
The study by Lehmann and colleagues provides a fascinating and unprecedented look at microRNA function in the brain. Typically, microRNAs function to regulate gene expression at the post-transcriptional level by targeting messenger RNAs, with known roles in neuronal maintenance, function, and survival. Here, however, the authors convincingly demonstrate that extracellular let-7 family members and, in particular, let-7b, function as ligands for the TLR7 receptor, known to play a fundamental role in pathogen recognition and activation of innate immunity. The TLR7 signaling cascade is activated through the conserved GUUGUGU motif located in let-7. Incubation of neurons with let-7b induced a dose- and time-dependent cell loss both in vitro and in vivo, an effect blocked in TLR7 knockout models. The authors identified caspase-3 as a mediator of neurodegeneration. Interestingly, neuronal loss could be induced using medium isolated from let-7 overexpressing HEK293 cells. Moreover, neuronal degeneration stimulated endogenous let-7 secretion, possibly contributing to a deleterious feedback loop. Finally, let-7b was significantly increased in CSF samples taken from Alzheimer’s disease (AD) patients. Obviously, this last observation raises several questions with regard to the potential role of let-7 family members, in addition to caspase activation and inflammation, in AD development. Previous studies have shown that let-7i was downregulated in AD brain and in biological models, likely a downstream effect of amyloid overproduction (1,2). On the other hand, and consistent with the current study, let-7f was previously shown to be upregulated in AD CSF (3). The possibility that neuronal microRNAs are secreted into the CSF under either physiological and/or pathological conditions remains to be fully explored. Clearly, this study adds to the growing list of publications suggesting that soluble microRNAs could provide important biomarkers for neurological diseases (3-5). The fact that microRNAs could function outside the cell adds to the complexity of this already multifaceted field.
Schonrock N, Ke YD, Humphreys D, Staufenbiel M, Ittner LM, Preiss T, Götz J.
Neuronal microRNA deregulation in response to Alzheimer's disease amyloid-beta.
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Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/beta-secretase expression.
Proc Natl Acad Sci U S A. 2008 Apr 29;105(17):6415-20.
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Identification of miRNA changes in Alzheimer's disease brain and CSF yields putative biomarkers and insights into disease pathways.
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In Vivo MicroRNA Detection and Quantitation in Cerebrospinal Fluid.
J Mol Neurosci. 2012 Mar 9;
Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, Maghnouj A, Zöllner H, Reinacher-Schick A, Schmiegel W, Hahn SA, Schroers R.
Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system.
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