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Biomarkers.

Rodrigo Sandoval1, Vladislav Novikov1, Anoosha Attaran2

  • 1University of Western Ontario, London, ON, Canada.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 26, 2025
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Summary
This summary is machine-generated.

Touchscreen cognitive tests improve preclinical drug evaluation for synucleinopathies. PU-AD showed broad neuroprotection, rescuing cognitive and motor deficits in mice, unlike Cinpanemab.

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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.