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Satir TM, Agholme L, Karlsson A, Karlsson M, Karila P, Illes S, Bergström P, Zetterberg H. Partial reduction of amyloid β production by β-secretase inhibitors does not decrease synaptic transmission. Alzheimers Res Ther. 2020 May 26;12(1):63. PubMed.
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University of Melbourne
Ever since the origin of Aβ was shown to be the result of proteolytic processing of the juxta-membranous and intramembranous domains of a beta-amyloid precursor protein (APP) (Kang et al., 1987), it has been apparent that this phenomenon must reflect some basic physiological function of APP and its superfamily partners (APLP1 and APLP2). Given its high neuronal expression and synaptic localization, most studies have concluded that the APP family plays a fundamental role in synaptic plasticity underlying learning and memory. Is it surprising, therefore, that high levels (more than 50 percent) of inhibition of either N-terminal (α- and β-secretases) and C-terminal (γ-secretase) processing should cause cognitive adverse effects?
Our studies (Roberts et al., 2017) indicated that over the 20-year natural history of AD (preclinical and prodromal stages), approximately 5 mg of Aβ peptide accumulates in the average AD brain. This represents a rate of accumulation of 28 ng/hour, which is approximately 5 percent of normal hourly production (Potter et al., 2013; Patterson et al., 2015). From this we would argue that if an inhibitor of production (either β- or γ-secretase) is used early enough in the pathogenesis of AD, a rate of inhibition on the order of 5 percent to 10 percent should be sufficient to prevent the abnormal accumulation of Aβ. Of course, higher levels of inhibition would be needed for interventions commencing at later stages of AD. In these circumstances, it would be logical to use an Aβ clearing agent (immunotherapy) followed by low dose inhibition maintenance therapy, close to the 5 percent levels of abnormal rates of accumulation.
Most compounds in the modern pharmacopoeia are toxic if given in sufficiently high doses. It’s good to see these BACE inhibitor (BACEi) in vitro results of Satir et al., which prove this point, and offer hope for re-examination of the potential benefits of these therapeutic strategies. Most of the clinical trials of BACEi have been operating at more than 70 percent to 80 percent inhibition levels. The biomarkers for Aβ-PET and p-tau changed in the right directions after relatively brief exposures. We must move forward and determine safe dosage levels, probably as a combination therapy of improved clearance followed by low dose maintenance inhibition of production.
References:
Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Müller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. PubMed.
Roberts BR, Lind M, Wagen AZ, Rembach A, Frugier T, Li QX, Ryan TM, McLean CA, Doecke JD, Rowe CC, Villemagne VL, Masters CL. Biochemically-defined pools of amyloid-β in sporadic Alzheimer's disease: correlation with amyloid PET. Brain. 2017 May 1;140(5):1486-1498. PubMed.
Potter R, Patterson BW, Elbert DL, Ovod V, Kasten T, Sigurdson W, Mawuenyega K, Blazey T, Goate A, Chott R, Yarasheski KE, Holtzman DM, Morris JC, Benzinger TL, Bateman RJ. Increased in vivo amyloid-β42 production, exchange, and loss in presenilin mutation carriers. Sci Transl Med. 2013 Jun 12;5(189):189ra77. PubMed.
Patterson BW, Elbert DL, Mawuenyega KG, Kasten T, Ovod V, Ma S, Xiong C, Chott R, Yarasheski K, Sigurdson W, Zhang L, Goate A, Benzinger T, Morris JC, Holtzman D, Bateman RJ. Age and amyloid effects on human central nervous system amyloid-beta kinetics. Ann Neurol. 2015 Sep;78(3):439-53. Epub 2015 Jul 20 PubMed.
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