The cellular prion protein (PrP C ) is a key neuronal receptor for β-amyloid oligomers (AβO), mediating their neurotoxicity, which contributes to the neurodegeneration in Alzheimer's disease (AD). Similarly to the amyloid precursor protein (APP), PrP C is proteolytically cleaved from the cell surface by a disintegrin and metalloprotease, ADAM10. We hypothesized that ADAM10-modulated PrP C shedding would alter the cellular binding and cytotoxicity of AβO. Here, we found that in human neuroblastoma cells, activation of ADAM10 with the muscarinic agonist carbachol promotes PrP C shedding and reduces the binding of AβO to the cell surface, which could be blocked with an ADAM10 inhibitor. Conversely, siRNA-mediated ADAM10 knockdown reduced PrP C shedding and increased AβO binding, which was blocked by the PrP C -specific antibody 6D11. The retinoic acid receptor analog acitretin, which up-regulates ADAM10, also promoted PrP C shedding and decreased AβO binding in the neuroblastoma cells and in human induced pluripotent stem cell (iPSC)-derived cortical neurons. Pretreatment with acitretin abolished activation of Fyn kinase and prevented an increase in reactive oxygen species caused by AβO binding to PrP C . Besides blocking AβO binding and toxicity, acitretin also increased the nonamyloidogenic processing of APP. However, in the iPSC-derived neurons, Aβ and other amyloidogenic processing products did not exhibit a reciprocal decrease upon acitretin treatment. These results indicate that by promoting the shedding of PrP C in human neurons, ADAM10 activation prevents the binding and cytotoxicity of AβO, revealing a potential therapeutic benefit of ADAM10 activation in AD.

Four out of 16 new allylic pyrophosphates synthesized were found to be artificial substrates for liver prenyltransferase (EC 2.5.1.1). These were the trans-and the cis-3-ethyl-3-methylallyl, the 3,3-diethylallyl and the (mixture of cis and trans) 3-methyl-3-n-propylallyl pyrophosphates. The products synthesized from these substrates and isopentenyl pyrophosphate were the appropriate homo- and bishomo-farnesyl pyrophosphates. Substitution of 3,3-dimethylallyl pyrophosphate at C-2 with a methyl group destroyed its reactivity with the enzyme. Neither the unsubstituted allyl pyrophosphate nor the cis- or trans-3-methylallyl pyrophosphate could be condensed with isopentenyl pyrophosphate. Thus the simplest allylic substrate for prenyltransferase is 3,3-dimethylallyl pyrophosphate.

The syntheses of 6,7-dihydrogeraniol and of its pyrophosphate are described. It is shown that this analogue of geranyl pyrophosphate is a substrate for liver prenyltransferase and that the product synthesized by this enzyme from it and isopentenyl pyrophosphate is 10,11-dihydrofarnesyl pyrophosphate. The K(m) value for 6,7-dihydrogeranyl pyrophosphate was determined to be 1.11+/-0.19mum as compared with 4.34+/-1.71mum for geranyl pyrophosphate. The maximum reaction velocity with the artifical substrate was, however, only about one-fourth of that observed with geranyl pyrophosphate. The binding of isopentenyl pyrophosphate to the enzyme was not affected by the artificial substrate.

Several substances have been shown to affect hepatic heme synthesis in the rat liver. Phenobarbital and the polycyclic hydrocarbon, 3,4-benzpyrene, produce an induction of aminolevulinic acid synthetase (ALAS), the enzyme mediating the first step in heme synthesis. This is followed sequentially by increased incorporation of glycine into microsomal heme, increased microsomal protoheme, cytochrome P-450, and increases in activity of certain microsomal mixed function oxidate reactions. Microsomal cytochrome b5 is not altered during such events. 3-amino-1,2,4-triazole inhibits increases in hepatic heme synthesis and drug oxidations produced by phenobarbital and 3,4-benzyprene, but has no effect on ALAS changes or cytochrome b5. Ferrochelatase, an enzyme mediating the last step in heme synthesis, is also increased by phenobarbital treatment. This enzyme was shown to be inhibited by lead and prior administration to the animal of 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine (DDC). DDC also induces ALAS activity. The combined increase in ALAS activity and inhibition of ferrochelatase by DDC could account for the profound porphyria produced by this agent. (Metabolism 20: No. 2, February, 200-214, 1971) C HRONIC TREATMENTOF ANIMALS WITH CERTAIN DRUGS, such as phenobarbital and carcinogens, such as 3,4-benzpyrene, results in the enhancement of a variety of hepatic microsomal 0xidations.l Stimulation of these oxidations appears to depend, in part, on increases in microsomal cytochrome P-450."," Recently, evidence has been presented which demonstrates that many agents, including phenobarbital and 3,4-benzpyrene, are capable of inducing hepatic S-aminolevulinic acid (ALA) synthetase,A-7 the proposed initial and rate-limiting enzyme in the hepatic heme biosynthetic pathway,ss" which could lead to an increased rate of synthesis of hepatic heme and which, in turn, might result in the increase of cytochrome P-450 and, in certain cases, the stimulation of certain hepatic microsomal drug oxidations. Previously, we have demonstrated that enhanced heme synthesis is essential for the induction of cytochrome P-450 and the stimulation of certain hepatic microsomal drug oxidations.i*10The present studies demonstrate the relationship between the stimulatory effects of phenobarbital and 3,4-benzpyrene on hepatic heme synthesis, cytochrome P-450, and ethylmorphine N-demethylation. Also, the effects of pheno-From the

The administration of either phenobarbital or 3,4-benzpyreue to rats resulted in the rapid and marked induction of 6-aminolevulinic acid synthetase (EC 2.3.1.13), the proposed initial and rate-limiting enzyme in the hepatic heme biosynthetic pathKay. Enhanced formation of 6-aminolevulinic acid was followed sequentially by an enhancement of t,he liver's capacity to synthesize microsomal heme in viva, irlcreases irl