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TFP5, a Peptide Inhibitor of Aberrant and Hyperactive Cdk5/p25, Attenuates Pathological Phenotypes and Restores

Varsha Shukla1, Jinsoo Seo2, B K Binukumar1

  • 1National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.

Journal of Alzheimer'S Disease : JAD
|January 14, 2017
PubMed

Insights

A novel peptide therapy targeting cyclin-dependent kinase 5 (cdk5) hyperactivity shows promise for Alzheimer's disease (AD). Injections reduced key AD pathologies and improved cognitive and motor functions in mice, suggesting a potential therapeutic strategy.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Pharmacology

Background:

  • Cyclin-dependent kinase 5 (cdk5) hyperactivity, often due to p25 overexpression, is implicated in Alzheimer's disease (AD) pathology, including amyloid plaques and neurofibrillary tangles (NFTs).
  • Previous studies indicated that a modified peptide (TFP5) could cross the blood-brain barrier and ameliorate AD-like pathology in mouse models.

Purpose of the Study:

  • To evaluate the efficacy of TFP5 in an inducible CK-p25Tg mouse model that overexpresses p25, a key driver of cdk5 hyperactivity in AD.
  • To assess TFP5's impact on cdk5 hyperactivity, tau and neurofilament phosphorylation, synaptic function, and behavioral deficits.

Main Methods:

  • Intraperitoneal (i.p.) injections of modified TFP5 were administered to CK-p25Tg mice.
  • Evaluations included measuring cdk5 hyperactivity, levels of hyperphosphorylated tau and neurofilament-M/H, synaptic function, and behavioral tests (spatial working memory, Rota-rod).

Main Results:

  • TFP5 injections successfully decreased cdk5 hyperactivity and reduced tau and neurofilament-M/H hyperphosphorylation in the treated mice.
  • The peptide treatment restored synaptic function and improved behavioral outcomes, including spatial working memory and motor coordination.
  • Importantly, TFP5 did not inhibit endogenous cdk5/p35 activity or other cyclin-dependent kinases (cdks) in vivo.

Conclusions:

  • The modified TFP5 peptide effectively targets p25-induced cdk5 hyperactivity and associated pathologies in a relevant AD mouse model.
  • TFP5 demonstrates therapeutic potential for neurodegenerative disorders characterized by elevated p25 and cdk5 activity, with a favorable safety profile due to its specificity.
Keywords:
Alzheimer’s diseaseTFP5cyclin-dependent kinase 5hyperphosphorylationsynaptic function

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