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Drug Development.

Toshiharu Suzuki1, Haruka Saito2, Shoichi Kinoshita2

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Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 25, 2025
PubMed
Summary
This summary is machine-generated.

The peptide p3-Alcß9-19, derived from Alcadeinß, shows potential in Alzheimer

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Area of Science:

  • Neuroscience and Neurodegenerative Diseases
  • Molecular Biology and Genetics
  • Pharmacology and Drug Discovery

Background:

  • Alcadeinß (Clstn3) is a synaptic membrane protein cleaved into peptides, including p3-Alcß37, p3-Alcß40, and p3-Alcß9-19.
  • These peptides, particularly p3-Alcß9-19, can restore mitochondrial function impaired by amyloid-beta oligomers in neuronal models and Alzheimer's disease (AD) mouse models.
  • Identifying molecular targets of p3-Alcß9-19 is crucial for understanding its therapeutic potential in AD.

Purpose of the Study:

  • To identify and validate the molecular targets of the peptide p3-Alcß9-19.
  • To analyze gene expression profiles in the brains of an AD mouse model treated with p3-Alcß9-19.
  • To investigate the therapeutic mechanisms of p3-Alcß9-19 in the context of AD-related gene expression changes.

Main Methods:

  • Administration of p3-Alcß9-19 (1mg/kg) to AppNL-F/NLF mice (an AD model) for one month.
  • RNA sequencing (RNAseq) analysis of dissected brain regions from treated mice and control (PBS-treated) mice.
  • Comparative analysis of gene expression changes in mouse models and human AD patients.

Main Results:

  • p3-Alcß9-19 administration altered gene expression in both neuronal and non-neuronal cells within the AD mouse brain.
  • Many genes downregulated in human AD patients were upregulated or showed a trend towards upregulation in p3-Alcß9-19-treated mice.
  • Conversely, some genes upregulated in human AD patients were normalized in the AD mouse model following p3-Alcß9-19 treatment.

Conclusions:

  • p3-Alcß9-19 protects neuronal functions by modulating gene expression profiles altered by pathogenic protein accumulation in the brain.
  • The peptide p3-Alcß9-19 demonstrates potential as a therapeutic agent for preserving brain homeostasis and combating neurodegeneration.
  • Preclinical findings support further clinical investigation of ALC919, a transdermal formulation of p3-Alcß9-19, for Alzheimer's disease treatment.