Related Experiment Video
Updated: Mar 8, 2026
A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging
Published on: July 14, 2016
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.
Abstract:
It has been reported that cyclin-dependent kinase 5 (cdk5), a critical neuronal kinase, is hyperactivated in Alzheimer's disease (AD) and may be, in part, responsible for the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs). It has been proposed by several laboratories that hyperactive cdk5 results from the overexpression of p25 (a truncated fragment of p35, the normal cdk5 regulator), which, when complexed to cdk5, induces hyperactivity, hyperphosphorylated tau/NFTs, amyloid-β plaques, and neuronal death. It has previously been shown that intraperitoneal (i.p.) injections of a modified truncated 24-aa peptide (TFP5), derived from the cdk5 activator p35, penetrated the blood-brain barrier and significantly rescued AD-like pathology in 5XFAD model mice. The principal pathology in the 5XFAD mutant, however, is extensive amyloid plaques; hence, as a proof of concept, we believe it is essential to demonstrate the peptide's efficacy in a mouse model expressing high levels of p25, such as the inducible CK-p25Tg model mouse that overexpresses p25 in CamKII positive neurons. Using a modified TFP5 treatment, here we show that peptide i.p. injections in these mice decrease cdk5 hyperactivity, tau, neurofilament-M/H hyperphosphorylation, and restore synaptic function and behavior (i.e., spatial working memory, motor deficit using Rota-rod). It is noteworthy that TFP5 does not inhibit endogenous cdk5/p35 activity, nor other cdks in vivo suggesting it might have no toxic side effects, and may serve as an excellent therapeutic candidate for neurodegenerative disorders expressing abnormally high brain levels of p25 and hyperactive cdk5.
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.
More Related Videos
10:38Author Spotlight: Understanding the Impact of Pathological Proteins on Axonal Transport in Neurodegenerative Diseases
Published on: December 22, 2023
09:13Author Spotlight: Identifying Compensatory Pathways in Malaria Parasites Containing Hypomorphic Allele of Essential Protein Kinases
Published on: November 22, 2024