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The anti-amyloid-β and neuroprotective properties of a novel tricyclic pyrone molecule


Year of Publication:
Contact PI Name:
Jin Lee-Way
Contact PI Affiliation:
Department of Pathology and Laboratory Medicine, University of California Davis Medical Center, Sacramento, California, USA
Izumi Maezawa, Bende Zou, Jacopo Di Lucente, William S. Cao, Conrado Pascual, Sahani Weerasekara, Man Zhang, Xinmin Simon Xie, Duy H. Hua
Primary Reference (PubMED ID):
Funding Source:
National Institute on Aging (NIA)
UC Davis Alzheimer’s Disease Center
Study Goal and Principal Findings:

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. Here was taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ 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-Aβ 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 Aβ, including both fibrillary and soluble Aβ 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 Aβ 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 h after administration. This 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.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Small Molecule
Therapeutic Agent:
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Model Type:
Strain/Genetic Background:
Model Type:
Strain/Genetic Background:
Not Reported
Model Type:
Strain/Genetic Background:
Not Applicable

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest


Outcome Measured
Outcome Parameters
Spontaneous Activity
Drinking Behavior
Motor Function
Rotarod Test
Locomotor Activity
beta Amyloid Load
Neuronal Loss
Binding-beta Amyloid Oligomers
Brain-Buffer Soluble beta Amyloid Peptides
Brain-Buffer Insoluble beta Amyloid Peptides
Amyloid Precursor Protein (APP)
Reactive Oxygen Species (ROS)
Cell Biology
Cell Viability
Long Term Potentiation (LTP)
field Excitatory Postsynaptic Potential (fEPSP)
Input/Output (I/O) Curve
Drug Concentration-Plasma
Drug Concentration-Brain
Drug Concentration-Organs
Area Under the Curve (AUC)
Oral Bioavailability (F%)
Cell Viability
Water Consumption
Lick Counts
Target Selectivity
Binding Affinity
Cerep Profile