{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T20:02:46Z","timestamp":1788379366319,"version":"build-2803163510"},"reference-count":60,"publisher":"SAGE Publications","issue":"2","license":[{"start":{"date-parts":[[2017,5,2]],"date-time":"2017-05-02T00:00:00Z","timestamp":1493683200000},"content-version":"unspecified","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Journal of Alzheimer\u2019s Disease"],"published-print":{"date-parts":[[2017,5,11]]},"abstract":"<jats:p>There is an urgent unmet need for new therapeutics for Alzheimer\u2019s disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-\u03b2 (A\u03b2) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-A\u03b2 and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-A\u03b2 therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral A\u03b2, including both fibrillary and soluble A\u03b2 species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the A\u03b2 oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24\u200ah after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.<\/jats:p>","DOI":"10.3233\/jad-161175","type":"journal-article","created":{"date-parts":[[2017,5,2]],"date-time":"2017-05-02T10:37:14Z","timestamp":1493721434000},"page":"559-574","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["The Anti-Amyloid-\u03b2 and Neuroprotective Properties of a Novel Tricyclic Pyrone Molecule"],"prefix":"10.1177","volume":"58","author":[{"given":"Izumi","family":"Maezawa","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, CA, 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