Drug Development

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Elevated phosphorylated tau (ptau) correlates with neurodegeneration in Alzheimer's disease (AD).
• Apolipoprotein E (ApoE) allele presence is a significant genetic risk factor for AD.
• Peroxisome proliferator-activated receptor delta (PPAR-δ) regulates neuronal metabolic processes, making it a potential therapeutic target for neurodegenerative diseases.

Purpose of the Study:

• To investigate the therapeutic effect of the PPAR-δ agonist T3D-959 on a mouse model of tauopathy (P301S/E4).
• To assess the impact of T3D-959 on neurological function and memory in the context of AD-related pathology.

Main Methods:

• T3D-959 was administered intraperitoneally (50mg/kg/day, 3x/week) to P301S/E4 mice from 4 to 11 months of age.
• Neurological and behavioral assessments, including Object Recognition Memory (ORM), Object Location Memory (OLM), and Y-maze tests, were conducted periodically.

Main Results:

• T3D-959 treated mice showed less weight deterioration compared to saline controls.
• Significant improvement in long-term memory was observed in T3D-959 treated mice during the Object Location Memory (OLM) test at 11 months (p=0.02).
• No significant differences were found in overall neurological scores, ORM, or Y-maze tests.

Conclusions:

• T3D-959 treatment significantly rescued long-term hippocampal memory function, as evidenced by superior OLM performance in treated mice.
• The findings suggest T3D-959 has a positive impact on the hippocampus, potentially preserving long-term memory in neurodegenerative conditions.
• OLM testing, which assesses transcription-based long-term memory, revealed the therapeutic benefits of T3D-959.