Abstract
Amyloid β42 (Aβ42), a causative agent of Alzheimer’s disease (AD), is derived extracellularly from Aβ precursor protein (APP) following the latter’s cleavage by β-secretase, but not α-secretase. Protein kinase Cα (PKCα) activation is known to increase α-secretase activity, thereby suppressing Aβ production. Since Aβ42 oligomer formation causes potent neurotoxicity, APP modulation by PKC ligands is a promising strategy for AD treatment. Although bryostatin-1 (bryo-1) is a leading compound for this strategy, its limited natural availability and the difficulty of its total synthesis impedes further research. To address this limitation, Irie and colleagues have developed a new PKC activator with few side effects, 10-Me-Aplog-1, (1), which decreased Aβ42 in the conditioned medium of rat primary cerebral cortex cells. These results are associated with increased α-secretase but not PKCε-dependent Aβ-degrading enzyme. The amount of neuronal embryonic lethal abnormal vision (nELAV), a known β-secretase stabilizer, was reduced by treatment with 1. Notably, 1 prevented the formation of intracellular toxic oligomers. Furthermore, 1 suppressed toxic oligomerization within human iPS-derived neurons such as bryo-1. Given that 1 was not neurotoxic toward either cell line, these findings suggest that 1 is a potential drug lead for AD therapy.
Highlights
The 40-mer and 42-mer amyloid β-proteins (Aβ40 and Amyloid β42 (Aβ42)) are considered causative agents of Alzheimer’s disease (AD) [1,2]
Aβ40 and Aβ42 are known to be produced from Aβ precursor protein (APP) following cleavage of the latter by β-secretase, but not α-secretase
Because the extracellular levels of toxic oligomers after a 24 h incubation were under the detection limit for specific ELISA (#27709 Human Amyloid β Toxic Oligomer Assay Kit—IBL) and Aβ42 aggregates to form amyloid fibrils after a 24 h incubation in vitro [35,36], we sampled at an earlier time point, 6 h, to determine the formation of toxic Aβ oligomers
Summary
The 40-mer and 42-mer amyloid β-proteins (Aβ40 and Aβ42) are considered causative agents of Alzheimer’s disease (AD) [1,2]. A mouse study demonstrated that PKCε activation reduces senile plaque formation, its effect on oligomer generation was not determined [13]. Since the amount of Aβ42 secreted by SH-SY5Y cells was near to the detection limit of specific ELISA (#27711 Human Amyloid β 1-42 Assay Kit—IBL), we selected rat primary cerebral cortex cells for evaluating PKC modulators in the following study. Because the extracellular levels of toxic oligomers after a 24 h incubation were under the detection limit for specific ELISA (#27709 Human Amyloid β Toxic Oligomer Assay Kit—IBL) and Aβ42 aggregates to form amyloid fibrils after a 24 h incubation in vitro [35,36], we sampled at an earlier time point, 6 h, to determine the formation of toxic Aβ oligomers. FigurFeig2u.r(ea).M(ao)nMomoneormiceAricβ4A2β, 4A2β, 4A0β,4a0n, dantdhetihreriratriaotio(A(Aβ4β24/2A/Aβ4β04)0)ininththeeccoonnddiittiioned mmeeddiiuummoof f rat primraartyprciemreabryraclerceobrrtaelxcocretlelxs cterellastterdeatwedithwi1tha1t atthteheininddicicaatteedd conncceennttrraatitoionnssfofro2r42h4. (hb.) (Tbo)xiTcoAxβic Aβ oligoomliegrosm, merso,nmomoneormiceAricβ4A2β, 4a2n,danthdetihreriartriaoti(oto(xtoicxiocloigliogmomeresr/sA/Aββ4422))inintthheeccoonnditionneeddmmeeddiuiummoof f rat primraartyprciemreabryraclerceobrrtaelxcocretlelxs cterlelastterdeatwedithwi1tha1t atthteheininddicicaatteedd conncceennttrraatitoionnssfofro6r h6. hT.heTdhaetadaartea are presepnretesednatesdmaseamnea±nS±DSD(n(=n =3)3. )*.*p**
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