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Hu X, Das B, Hou H, He W, Yan R. BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med. 2018 Mar 5;215(3):927-940. Epub 2018 Feb 14 PubMed.
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German Center for Neurodegenerative Diseases (DZNE)
This is a very interesting study that provides several important advances and insights for the field. It is particularly intriguing to see that BACE1 inhibition not only reduces plaque growth, but may even shrink existing plaques. If it also happens in patients this would be fantastic news for the clinical trials with BACE inhibitors. Because AD mouse models, including the 5xFAD model used in this study, typically mimic presymptomatic AD, it would appear possible that secondary prevention trials with BACE inhibitors may not only yield reduced growth or number of plaques, but even a shrinking of pre-existing plaques and a reduction of neuroinflammation—provided that the drugs are given early enough before the symptoms start. This should and will be tested in the trials’ participants using PET imaging. These new findings contradict a recent study that demonstrated that plaques remain stable in size when BACE1 is inhibited pharmacologically. I am sure that this discrepancy will be resolved with future experiments and may depend on the mouse line used, or the level or duration of BACE1 inhibition.
We also need to consider that the amazing effects of the mouse study were accompanied by an intriguingly gradual reduction of BACE1 protein levels. It is difficult to predict exactly which inhibition level of BACE1 would be needed in humans to achieve the same results. Potentially, the levels currently used in trials are already sufficient.
Another take-home message of the study is that memory and LTP deficits were improved in the AD mice as BACE1 was suppressed. While this is good news, the study also demonstrated that LTP did not fully recover. This indicates that the therapeutically desired BACE inhibition in adult mice may interfere with physiological BACE1 functions. Besides LTP, this includes muscle spindle formation/maintenance and dendritic spine densities in adult mice. Translated to humans, this could indicate a larger number of falls or psychiatric symptoms in individuals treated with BACE inhibitors. Whether this is a realistic concern will be seen from the results of the currently ongoing and recently terminated BACE inhibitor trials.
Constitutive BACE1-deficient mice show a number of different phenotypes. Another major insight of the new study is that adult deletion of BACE1 overcomes at least one of the symptoms—the hypomyelination. The new conditional BACE1-deficient mice are an excellent tool to analyze whether the other BACE1-deficient mouse phenotypes are also of developmental origin and which functions of BACE1 are relevant in adult mice. Taken together, the new study is an excellent basis both for basic and translational BACE1 research.
View all comments by Stefan LichtenthalerI am interested to know why, under BACE1 cKO, there is, in addition to an expected decrease in C99, a decrease in C83 as well. The authors suggest that a cKO of BACE1 improves autophagy, increasing turnover of C-terminal fragments. However, there is no change in C83 in the original KO (Cai, 2001). Have the authors looked at APP trafficking in their model? I would be interested to know if the amount of sAPPα is the same, i.e. is APP still being trafficked to the cell surface?
References:
Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, Wong PC. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci. 2001 Mar;4(3):233-4. PubMed.
View all comments by Marc TambiniUniversity of Connecticut Health
The collaborative team of Drs. Herms and Neumann published a nice study on the use of NB-360 to block formation of new plaques. The main difference between their study and ours is the chemical inhibition of versus the sequential deletion of BACE1 in AD mouse models. It is understood that chemical inhibition of BACE1 may never reach the level of near-complete deletion of BACE1 in mouse brains. In mice with conditional deletion of BACE1, BACE1 protein was barely detectable and its activity is diminished to the extent of drastically decreased APP-C99 and Aβ levels.
The reason for the reversal of amyloid plaques, evidenced not only by 6E10 staining of plaques but also staining by thioflavin S and an anti-Aβ42 antibody (AB-2341375 from IBL), is not fully understood yet, but is actively being investigated in the lab. As pointed out by Marc Tambini, it is intriguing and counterintuitive to see the observed reduction of APP-C83. Presenting a counterintuitive result is important for motivating a novel finding. When we first overexpressed BACE1 in cultured cells expressing Swedish APP, we actually observed reduction of Aβ1-40 and Aβ1-42 levels rather than an expected increase (Figure 4a in Yan et al. 1999), and this counterintuitive result led to the discovery of β'-cleavage.
References:
Yan R, Bienkowski MJ, Shuck ME, Miao H, Tory MC, Pauley AM, Brashier JR, Stratman NC, Mathews WR, Buhl AE, Carter DB, Tomasselli AG, Parodi LA, Heinrikson RL, Gurney ME. Membrane-anchored aspartyl protease with Alzheimer's disease beta-secretase activity. Nature. 1999 Dec 2;402(6761):533-7. PubMed.
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