PMC:6582309 / 54414-56517 JSONTXT

{"project":"2_test","denotations":[{"id":"31249505-25609634-38601760","span":{"begin":281,"end":285},"obj":"25609634"},{"id":"31249505-25609634-38601761","span":{"begin":387,"end":391},"obj":"25609634"},{"id":"31249505-22328928-38601762","span":{"begin":597,"end":601},"obj":"22328928"},{"id":"31249505-22328928-38601763","span":{"begin":819,"end":823},"obj":"22328928"},{"id":"31249505-30224383-38601764","span":{"begin":1068,"end":1072},"obj":"30224383"},{"id":"31249505-22004509-38601765","span":{"begin":1266,"end":1270},"obj":"22004509"},{"id":"31249505-22004509-38601766","span":{"begin":1388,"end":1392},"obj":"22004509"},{"id":"31249505-9307048-38601767","span":{"begin":1528,"end":1532},"obj":"9307048"},{"id":"31249505-8771606-38601768","span":{"begin":1602,"end":1606},"obj":"8771606"},{"id":"31249505-19753696-38601769","span":{"begin":1782,"end":1786},"obj":"19753696"},{"id":"31249505-12535396-38601770","span":{"begin":1949,"end":1953},"obj":"12535396"}],"text":"BACE1 is a protease that controls the formation of Aβ and most likely plays an important role in the development of pathogenesis in AD. The usefulness of BACE1 small-molecule inhibitor LY2886721 has been tested in a dog model and in humans in the first clinical phase (May et al., 2015). It significantly reduced plasma and CSF Aβ levels both in dogs and healthy volunteers (May et al., 2015). After administration of two BACE1 inhibitors (cyclic sulfoxide hydroxyethylamine NB-B4 and oxazine derivative NB-C8) a unique pattern of secreted Aβ peptides was observed in canine CSF (Mattsson et al., 2012). Besides the expected reduced levels of Aβ40 and Aβ42, reduced levels of Aβ1–34 and increased levels of Aβ5–40 were detected, which were proposed as prognostic markers of BACE1 inhibition therapies (Mattsson et al., 2012). A recent survey, using BACE1 inhibitor CNP520, demonstrated reduced brain and CSF Aβ in rats, dogs, and reduced CSF Aβ in humans and was assessed to be well tolerated in healthy adults and further clinical trials are ongoing (Neumann et al., 2018). A cardiovascular disease drug, atorvastatin, has been investigated in a canine model of dementia whether it could reduce Aβ plaques, BACE1 protein levels and oxidative stress (Barone et al., 2012). It does offer some neuroprotective role through the up-regulation of enzyme biliverdin reductase-A (Barone et al., 2012). Selegiline (L-deprenyl), a type B monoamine oxidase inhibitor, has been reported to prolong the survival of aged dogs (Ruehl et al., 1997) and in some cases improve visuospatial working memory (Head et al., 1996). However, in subsequent studies only a small subset of dogs seemed to show improvement, pointing to a minor clinical relevance of selegiline administration (Campbell et al., 2001). Furthermore, several human AD trials provided no evidence of clinically meaningful benefits of selegiline administration for people with AD (Birks and Flicker, 2003). Interestingly, although selegiline was shown to be fairly ineffective in the treatment of CCD, it is still the only FDA-approved treatment for CCD."}

{"project":"0_colil","denotations":[{"id":"31249505-25609634-737185","span":{"begin":281,"end":285},"obj":"25609634"},{"id":"31249505-25609634-737186","span":{"begin":387,"end":391},"obj":"25609634"},{"id":"31249505-22328928-737187","span":{"begin":597,"end":601},"obj":"22328928"},{"id":"31249505-22328928-737188","span":{"begin":819,"end":823},"obj":"22328928"},{"id":"31249505-30224383-737189","span":{"begin":1068,"end":1072},"obj":"30224383"},{"id":"31249505-22004509-737190","span":{"begin":1266,"end":1270},"obj":"22004509"},{"id":"31249505-22004509-737191","span":{"begin":1388,"end":1392},"obj":"22004509"},{"id":"31249505-9307048-737192","span":{"begin":1528,"end":1532},"obj":"9307048"},{"id":"31249505-8771606-737193","span":{"begin":1602,"end":1606},"obj":"8771606"},{"id":"31249505-19753696-737194","span":{"begin":1782,"end":1786},"obj":"19753696"},{"id":"31249505-12535396-737195","span":{"begin":1949,"end":1953},"obj":"12535396"}],"text":"BACE1 is a protease that controls the formation of Aβ and most likely plays an important role in the development of pathogenesis in AD. The usefulness of BACE1 small-molecule inhibitor LY2886721 has been tested in a dog model and in humans in the first clinical phase (May et al., 2015). It significantly reduced plasma and CSF Aβ levels both in dogs and healthy volunteers (May et al., 2015). After administration of two BACE1 inhibitors (cyclic sulfoxide hydroxyethylamine NB-B4 and oxazine derivative NB-C8) a unique pattern of secreted Aβ peptides was observed in canine CSF (Mattsson et al., 2012). Besides the expected reduced levels of Aβ40 and Aβ42, reduced levels of Aβ1–34 and increased levels of Aβ5–40 were detected, which were proposed as prognostic markers of BACE1 inhibition therapies (Mattsson et al., 2012). A recent survey, using BACE1 inhibitor CNP520, demonstrated reduced brain and CSF Aβ in rats, dogs, and reduced CSF Aβ in humans and was assessed to be well tolerated in healthy adults and further clinical trials are ongoing (Neumann et al., 2018). A cardiovascular disease drug, atorvastatin, has been investigated in a canine model of dementia whether it could reduce Aβ plaques, BACE1 protein levels and oxidative stress (Barone et al., 2012). It does offer some neuroprotective role through the up-regulation of enzyme biliverdin reductase-A (Barone et al., 2012). Selegiline (L-deprenyl), a type B monoamine oxidase inhibitor, has been reported to prolong the survival of aged dogs (Ruehl et al., 1997) and in some cases improve visuospatial working memory (Head et al., 1996). However, in subsequent studies only a small subset of dogs seemed to show improvement, pointing to a minor clinical relevance of selegiline administration (Campbell et al., 2001). Furthermore, several human AD trials provided no evidence of clinically meaningful benefits of selegiline administration for people with AD (Birks and Flicker, 2003). Interestingly, although selegiline was shown to be fairly ineffective in the treatment of CCD, it is still the only FDA-approved treatment for CCD."}