Biomarkers

Area of Science:

• Neuroscience
• Pharmacology
• Drug Development

Background:

• Neurodegenerative diseases like Alzheimer's and Parkinson's involve misfolded protein accumulation (amyloid-β, tau, alpha-synuclein).
• Current therapies are not disease-modifying, and animal models often lack predictive validity for clinical efficacy.
• Cognitive deficits, such as impaired reversal learning, are seen in synucleinopathies, highlighting the need for cognitive biomarkers in preclinical testing.

Purpose of the Study:

• To evaluate if touchscreen-based cognitive testing enhances the predictive validity of preclinical drug testing for synucleinopathies.
• To assess the efficacy of PU-AD, an HSP90 epichaperome disruptor, and Cinpanemab, an anti-alpha-synuclein antibody, in a mouse model of synucleinopathy.

Main Methods:

• Mice (M83) were injected with alpha-synuclein preformed fibrils (PFFs) to induce synucleinopathy.
• Cognitive flexibility was assessed using the Pairwise Visual Discrimination and Reversal (PVD-R) touchscreen task.
• PU-AD and Cinpanemab were administered, and cognitive, motor, pathological, and neuroinflammatory outcomes were evaluated.

Main Results:

• Mice with synucleinopathy exhibited earlier cognitive deficits than motor impairments.
• PU-AD treatment significantly improved both cognitive and motor functions, indicating neuroprotective effects.
• Cinpanemab treatment did not improve cognitive or motor symptoms, aligning with failed clinical trials.

Conclusions:

• Touchscreen cognitive testing improved the predictive validity of preclinical drug evaluation for synucleinopathies.
• PU-AD demonstrated broad therapeutic potential by ameliorating both cognitive and motor impairments.
• The study highlights the limitations of certain drug candidates (e.g., Cinpanemab) in preclinical models and the value of cognitive assessments.