The 75 kDa neurotrophin receptor (p75NTR) and two neurotrophin receptor homologs (NRH1, NRH2) constitute a subfamily of the nerve growth factor/tumor necrosis factor receptor superfamily. NRH1 coexists with p75NTR in fish, amphibians, and birds but is absent in mammals, whereas NRH2 exists only in mammals. Unlike p75NTR and NRH1, NRH2 lacks a canonical extracellular ligand binding domain. The similarity of NRH2 to the product of metalloproteinase cleavage of p75NTR prompted us to examine the cleavage of p75NTR in greater detail. p75NTR, NRH1, and NRH2 undergo multiple proteolytic cleavages that ultimately release cytoplasmic fragments. For p75NTR, cleavage in the extracellular domain by a PMA-inducible membrane metalloproteinase is followed by cleavage within or near the transmembrane domain, releasing the intracellular domain into the cytoplasm. This processing resembles the alpha- and gamma-secretase-mediated processing of beta-amyloid precursor protein and the similar processing of Notch. Although neurotrophins did not regulate p75NTR processing, the alpha- and gamma-secretase-mediated cleavage of p75 is modulated by receptor tyrosine kinases (Trks) TrkA and TrkB but not TrkC. Surprisingly, although NRH1 and NRH2 also undergo proteolytic cytoplasmic release of intracellular domains, a different protease mediates the cleavage. Furthermore, whereas the p75NTR soluble intracellular domain accumulates only in the presence of proteasome inhibitors, the equivalent fragment of NRH2 is stable and localizes in the nucleus. Because soluble intracellular domains of p75NTR and NRH2 were found to activate NF-kappaB in concert with TNF receptor associated factor 6 (TRAF6), we propose that cleavage of these proteins may serve conserved cytoplasmic and nuclear signaling functions through distinct proteases.

Our results support the findings of recent pangenomic studies that true polysomy 17 is uncommon. Additional FISH studies that use probes to the SMS, RARA, and TP53 genes are an effective way to determine the true HER2 amplification status in patients with polysomy 17 and they have important potential implications for guiding HER2-targeted therapy in breast cancer.

Cleavage of the b-secretase processed b-amyloid precursor protein by c-secretase leads to the extracellular release of Ab42, the more amyloidogenic form of the b-amyloid peptide, which subsequently forms the amyloid-plaques diagnostic of Alzheimer's disease. Mutations in b-amyloid precursor protein (APP), presenilin-1 and presenilin-2 associated with familial Alzheimer's disease (FAD) increase release of Ab42, suggesting that FAD may directly result from increased c-secretase activity. Here, we show that familial Alzheimer's disease mutations clustered near the sites of c-secretase cleavage actually decrease c-secretase-mediated release of the intracellular fragment of APP (CTFc). Concordantly, presenilin-1 mutations that result in Alzheimer's disease also decrease the release of CTFc. Mutagenesis of the epsilon cleavage site in APP mimicked the effects of the FAD mutations, both decreasing CTFc release and increasing Ab42 production, suggesting that perturbation of this site may account for the observed decrement in c-secretase-mediated proteolysis of APP. As CTFc has been implicated in transcriptional activation, these data indicate that decreased signaling and transcriptional regulation resulting from FAD mutations in bamyloid precursor protein and presenilin-1 may contribute to the pathology of Alzheimer's disease. Familial Alzheimer's disease (FAD) is an autosomal dominant disorder caused by missense mutations in b-amyloid precursor protein (APP), presenilin-1 (PS1) and presenilin-2 (PS2) (Selkoe 2001). APP is a type I transmembrane protein that is sequentially proteolytically processed by a-, b-, and c-secretase. APP cleavage by a-secretase results in the release of the large extracellular domain and the generation of the C83 membrane-resident fragment. b-secretase cleavage of APP, mediated by the BACE atypical aspartyl protease (Vassar et al. 1999), also liberates the extracellular domain and generates the C99 membrane-resident fragment. Subsequently, C83 and C99 are processed by the recently characterized heterotetrameric c-secretase complex consisting of Nicastrin, Aph-1, Pen-2, and PS1/2 (Francis et al. 2002;Edbauer et al. 2003;Kimberly et al. 2003;Takasugi et al. 2003). c-Secretase cleavage of C83 and C99 produces the innocuous p3 peptide and the pathogenic Ab peptide, respectively, and releases the intracellular fragment of APP from the membrane (referred to in this work as CTFc). PS1 and PS2 form the catalytic core for the c-secretase processing of APP (Schroeter et al. 2003;Cervantes et al. 2004). Generation of FAD pathology by mutations in either the APP substrate or the PS1/2 cleaving enzyme indicates that the etiology of the disorder resides in some alteration in the enzyme-substrate relationship.Multiple alternative sites of cleavage of APP by c-secretase generate a variety of Ab peptides, of which Ab40 and Ab42 are the most studied. The FAD mutations in

SummaryTrafficking through the secretory pathway is known to regulate the maturation of the APP-cleaving secretases and APP proteolysis. The coupling of stress signaling and pathological deterioration of the brain in Alzheimer's disease (AD) supports a mechanistic connection between endoplasmic reticulum (ER) stress and neurodegeneration. Consequently, small molecular chaperones, which promote protein folding and minimize ER stress, might be effective in delaying or attenuating the deleterious progression of AD. We tested this hypothesis by treating APPswePS1delta9 AD transgenic mice with the molecular chaperone phenylbutyric acid (PBA) for 14 months at a dose of 1 mg PBA g)1 of body weight in the drinking water. Phenylbutyric acid treatment increased secretasemediated APP cleavage, but was not associated with any increase in amyloid biosynthesis. The PBA-treated AD transgenic mice had significantly decreased incidence and size of amyloid plaques throughout the cortex and hippocampus. There was no change in total amyloid levels suggesting that PBA modifies amyloid aggregation or pathogenesis independently of biogenesis. The decrease in amyloid plaques was paralleled by increased memory retention, as PBA treatment facilitated cognitive performance in a spatial memory task in both wild-type and AD transgenic mice. The molecular mechanism underlying the cognitive facilitation of PBA is not clear; however, increased levels of both metabotropic and ionotropic glutamate receptors, as well as ADAM10 and TACE, were observed in the cortex and hippocampus of PBA-treated mice. The data suggest that PBA ameliorates the cognitive and pathological features of AD and supports the investigation of PBA as a therapeutic for AD.