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Willem M, Tahirovic S, Busche MA, Ovsepian SV, Chafai M, Kootar S, Hornburg D, Evans LD, Moore S, Daria A, Hampel H, Müller V, Giudici C, Nuscher B, Wenninger-Weinzierl A, Kremmer E, Heneka MT, Thal DR, Giedraitis V, Lannfelt L, Müller U, Livesey FJ, Meissner F, Herms J, Konnerth A, Marie H, Haass C. η-Secretase processing of APP inhibits neuronal activity in the hippocampus. Nature. 2015 Oct 15;526(7573):443-7. Epub 2015 Aug 31 PubMed.
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Northwestern University Feinberg School of Medicine
The discovery of η-secretase processing of APP is an intriguing finding that may have important implications for BACE inhibition as a therapeutic approach for AD. Willem and colleagues convincingly show that BACE inhibition increases the Aη-α fragment in vitro and in vivo, and furthermore demonstrate that Aη-α impairs hippocampal LTP and reduces neuronal activity. Aη-β, which is shorter than Aη-α at the C-terminus by only 16 amino acids, does not appear to have negative effects on LTP or neuronal activity; it would be very interesting to determine why this is the case. It will also be important to characterize η-secretase processing of APP in humans and how BACE inhibition affects the balance between Aη-α and Aη-β in individuals subjected to BACE inhibition. Clearly, this is an important new area of AD research that requires further investigation. We, as a field, should pay close attention to it as we move forward with BACE inhibitors in clinical trials.
View all comments by Robert VassarInstitut de Pharmacologie Moléculaire et Cellulaire
The paper by Willem et al. is an interesting study on APP processing, showing that current canonical views about APP-related cleavage events are likely a very partial understanding of the overall process. It shows that an additional cleavage, occurring upstream of the BACE-1-dependent proteolysis, generates an η-CTF fragment. This η cleavage is mediated by a matrixine named MT5-MMP. This set of data are in line with our recent study performed with Dr. Santiago Rivera and colleagues (Baranger et al., 2015) showing that MT5-MMP behaved as a new pro-amyloidogenic APP-cleaving enzyme generating an sAPP95 N-terminal fragment that could well correspond to the N-terminal counterpart of η-CTF. One interesting point of Willem’s study is that η-CTF generated by MT5-MMP-mediated primary cleavage undergoes subsequent secondary proteolysis by β- and α-secretases, yielding Aη-β and Aη-α, respectively. Interestingly, only the latter can trigger hippocampal defects, illustrated by altered LTP. This agrees very well with our data showing that knocking out MT5-MMP in 5XTg mice restores LTP to normal.
BACE-1 blockade is reported to enhance η-CTF and Aη-α, and to lower hippocampal LTP in mice. The latter set of data challenges the notion that BACE1 inhibition rescues Alzheimer’s-like pathology and cognitive defects in transgenic animals and, at a glance, is at odds with a pathogenic Aη-α production enhanced upon BACE-1 blockade. Furthermore, it questions current views on secretase functions and raises several puzzling questions. Is β-secretase-mediated cleavage of APP beneficial and α-secretase cleavage deleterious? Is η-CTF, per se, an APP product of a pathogenic processing pathway, or is it just a precursor of subsequent toxic fragments including Aη-α, or is it both? Our previous work did not address this question, but clearly demonstrated that depletion of endogenous MT5-MMP-mediated cleavage not only improved amyloid pathology but also ameliorated hippocampal currents, inflammation stigmata, and cognitive deficits. These paradigms were not addressed in Willem and colleagues' paper, but should be examined by means of constructs expressing each of the putative pathogenic triggers linked to η-secretase cleavage and subsequent products. This is of utmost importance for both the fundamental understanding of APP processing and for an industry committed to selective and potent inhibitors directed against BACE-1.
References:
Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier JM, Py NA, Bernard A, Bauer C, Charrat E, Moschke K, Seiki M, Vignes M, Lichtenthaler SF, Checler F, Khrestchatisky M, Rivera S. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease. Cell Mol Life Sci. 2016 Jan;73(1):217-36. Epub 2015 Jul 23 PubMed.
View all comments by Frédéric CheclerCNRS/Aix-Marseille University
This interesting study by Willem and colleagues reinforces data we published in July (Baranger et al., 2015). Our study, a collaboration with Drs. Checler and Vignes (France), Lichtenthaler (Germany), and Seiki (Japan), shows that knockout of MT5-MMP in the 5xFAD model drastically drops the levels of Aβ and the C99 APP C-terminal fragment derived from β-secretase cleavage. MT5-MMP deletion in our bigenic mice attenuates neuroinflammation and prevents LTP dysfunction and learning deficits.
The results of Willem and colleagues in cultured neurons provide an additional mechanistic explanation for our in vivo observation: the generation of a CTFη fragment of ~30 kDa that is further processed by α- or β-secretase to generate in the first case a neurotoxic peptide Aη-α that interferes with LTP and synaptic activity. In contrast, the β-secretase-derived Aη-β product would be innocuous. This raises a provocative question on whether the activity of α-secretase would be detrimental upon BACE inhibition.
In our study, we do not consistently detect the ~30 kDa fragment, but we detect a 6E10+ ~12 kDa band that may represent a trimer of Aβ. Alternatively, we suggested that this band could correspond to an N-terminally elongated Aβ form cleaved by MT5-MMP and secretases. Whether the ~12 kDa band we observe is the Aη-α fragment reported in the Willem paper needs to be further evaluated. In any case, it turns out to be dramatically decreased in the brains of our bigenic 5xFAD/MT5-MMP-/- mice, indicating a clear effect of MT5-MMP in vivo. Further evidence that MT5-MMP may process APP in vivo stems from the decrease of the 90 kDa N-terminal soluble APP form that we observed in bigenic 5xFAD/MT5-MMP-/- mice, and which was reported by Willem and colleagues to migrate around 80 kDa.
Together, the Baranger and the Willem studies independently highlight the importance of MT5-MMP as an APP-processing enzyme with potential pathophysiological and translational relevance in Alzheimer’s disease. On one hand, our data demonstrate that the improved pathophysiological outcome upon MT5-MMP deficiency in AD mice occurs without alterations in the activities of β- and γ-secretases. This is important to the prospect of achieving “safe” pharmacological inhibition of MT5-MMP without the side effects commonly associated with the inhibition of β- and γ-secretases. On the other hand, the detection of the Aη-α neurotoxic fragment in CSF and brain reported by Willem and colleagues provides a biomarker for indirect monitoring of MT5-MMP activity, as well as a potential therapeutic target on its own.
From the above it follows that modulating the activity of MT5-MMP or other MT-MMPs that share the cleavage site on APP (see our recent paper on MT1-MMP, Py et al., 2014) may open the way to designing complementary therapeutic strategies to those currently being developed. However, a necessary prerequisite is to have comprehensive knowledge of MT5-MMP physiological activities, its substrates, and its molecular interactions with key elements of the amyloidogenic cascade.
References:
Baranger K, Marchalant Y, Bonnet AE, Crouzin N, Carrete A, Paumier JM, Py NA, Bernard A, Bauer C, Charrat E, Moschke K, Seiki M, Vignes M, Lichtenthaler SF, Checler F, Khrestchatisky M, Rivera S. MT5-MMP is a new pro-amyloidogenic proteinase that promotes amyloid pathology and cognitive decline in a transgenic mouse model of Alzheimer's disease. Cell Mol Life Sci. 2016 Jan;73(1):217-36. Epub 2015 Jul 23 PubMed.
Py NA, Bonnet AE, Bernard A, Marchalant Y, Charrat E, Checler F, Khrestchatisky M, Baranger K, Rivera S. Differential spatio-temporal regulation of MMPs in the 5xFAD mouse model of Alzheimer's disease: evidence for a pro-amyloidogenic role of MT1-MMP. Front Aging Neurosci. 2014;6:247. Epub 2014 Sep 18 PubMed.
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