Hook G, Hook V, Kindy M.
The cysteine protease inhibitor, E64d, reduces brain amyloid-β and improves memory deficits in Alzheimer's disease animal models by inhibiting cathepsin B, but not BACE1, β-secretase activity.
J Alzheimers Dis. 2011;26(2):387-408.
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Aβ-lowering effects of E64d are very intriguing. However, since E64d inhibits numerous cathepsins, the mechanism by which E64d lowers Aβ remains unclear. Moreover, given the recent finding from Randy Nixon's group that inhibitors of cathepsins, including E64, disrupt axonal transport and cause axonal dystrophic swelling (Lee et al., 2011), one needs to be very cautious about this approach.
The Hook lab has suggested in the past that cathepsin B (CatB) only acts as a β-secretase with wild-type human APP (see Hook comment on Mueller-Steiner et al., 2006). We have deleted and overexpressed CatB in hAPP-I63 mice, which overexpress wild-type human APP. In our analyses of these mice, which will be presented this fall at the Society for Neuroscience meeting in Washington, DC, deletion or overexpression of CatB in neurons had no effect on β-CTF derived from wild-type hAPP. In contrast, deleting CatB increased Aβ while overexpressing CatB reduced it. Consistent with these findings, deleting cystatin C (an endogenous inhibitor of cathepsin B) in hAPP-I63 mice lowered Aβ levels.
Furthermore, consistent with our findings on cystatin C deletion, Randy Nixon's group reported that deletion of cystatin B (another endogenous inhibitor of cathepsins, including CatB) led to reduction of Aβ and plaques in TgCRND8 AD transgenic mice (Yang et al., 2011). These findings contrast with the effects of E64d, which has been shown to inhibit numerous lysosomal proteases (Barrett et al., 1982).
Lee S, Sato Y, Nixon RA.
Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer's-like axonal dystrophy.
J Neurosci. 2011 May 25;31(21):7817-30.
Mueller-Steiner S, Zhou Y, Arai H, Roberson ED, Sun B, Chen J, Wang X, Yu G, Esposito L, Mucke L, Gan L.
Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer's disease.
Neuron. 2006 Sep 21;51(6):703-14.
Yang DS, Stavrides P, Mohan PS, Kaushik S, Kumar A, Ohno M, Schmidt SD, Wesson D, Bandyopadhyay U, Jiang Y, Pawlik M, Peterhoff CM, Yang AJ, Wilson DA, St George-Hyslop P, Westaway D, Mathews PM, Levy E, Cuervo AM, Nixon RA.
Reversal of autophagy dysfunction in the TgCRND8 mouse model of Alzheimer's disease ameliorates amyloid pathologies and memory deficits.
Brain. 2011 Jan;134(Pt 1):258-77.
Barrett AJ, Kembhavi AA, Brown MA, Kirschke H, Knight CG, Tamai M, Hanada K.
L-trans-Epoxysuccinyl-leucylamido(4-guanidino)butane (E-64) and its analogues as inhibitors of cysteine proteinases including cathepsins B, H and L.
Biochem J. 1982 Jan 1;201(1):189-98.
The primary outcome data from the reaZin study appear to be consistent with the proposed action of the intervention. The three cognitive and functional measures used for the series of secondary outcomes are appropriate, but the small size of the sample means that the study was underpowered with respect to any clinical outcome measures. The small sample size was probably responsible also for the lack of balance in baseline measures across the randomized groups. Whether one should see the preliminary clinical outcome results as encouraging is a matter of judgment. The poster presentation does not make it clear whether the composite outcome was specified a priori. If not, the meaning of the p-value of 0.15 is hard to discern. In any event, I cannot agree with the authors' conclusion that these results provide a "strong trend toward cognitive benefit favoring the treatment group."
Dr. Gan’s comments do not address the main point of our paper, which is that oral E64d improves memory in an AD mouse model that represents the majority of AD patients. Feeding E64d-containing chow to transgenic APPL on AD mice improved memory and reduced both Aβ and amyloid plaques in brain. Furthermore, guinea pigs that express human wild-type APP show reduced brain Aβ after oral administration of E64d. Because E64d has been shown to be safe in patients at the effective dose used in the animal experiments, this compound can be tested in the clinic for AD.
Dr. Gan makes an excellent comment about E64d inhibition of cathepsins. We, too, discuss the multiple beneficial effects of E64d on inhibition of several cysteine cathepsins as well as calpain. These properties result in reduction of toxic Aβ and neuroprotection.
Dr. Gan’s point on potential mechanisms of drug action is impossible to evaluate. She cites unpublished data from her lab, but we cannot evaluate data not shown. Therapeutic agents can improve the human disease condition without knowledge of their mechanism. Many drugs are used for disease treatments for which mechanisms of action are unknown or controversial, for example, lithium for bipolar disorder.
The key finding about E64d is that it is efficacious at improving memory in animal models expressing APP with the wild-type β-secretase site that is expressed in the majority of AD patients.
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