Small Peptide Cures Alzheimer's Disease in Mouse Model by Blocking Cyclin-Dependent Kinase 5 Activity

Investigators at the [US] National Institutes of Health (Bethesda, MD, USA) prepared a 24-amino acid peptide (TFP5) derived from the Cdk5 activator p35. The p35protein is a neuron-specific activator of CDK5; the activation of CDK5 is required for proper development of the central nervous system. The p35 form of this protein is proteolytically cleaved by calpain, generating a p25 form. The cleavage of p35 into p25 results in relocalization of the protein from the cell periphery to nuclear and perinuclear regions. P25 deregulates CDK5 activity by prolonging its activation and changing its cellular location. The p25 form accumulates in the brain neurons of AD patients. This accumulation correlates with an increase in CDK5 kinase activity, and may lead to aberrantly phosphorylated forms of the microtubule-associated protein tau, which contributes to Alzheimer's disease.

The investigators injected TFP5 into a group of 5XFAD mice, an animal model that closely mimics human AD. Other 5XFAD mice were injected with either saline or scrambled peptide placebos.

Results published in the January 2013 issue of the FASEB Journal revealed that TFP5 penetrated the blood-brain barrier, inhibited abnormal Cdk5 hyperactivity, and reversed AD pathology by up to 70%–80%.

The mice injected with TFP5 exhibited behavioral rescue, whereas no rescue was observed in the mice injected with either saline or scrambled peptide. Nonetheless, TFP5 did not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby had no toxic side effects. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and life span extended by two months.

The results suggest that TFP5 may be a potential therapeutic, toxicity-free candidate for AD. "We hope that clinical trial studies in AD patients should yield an extended and a better quality of life as observed in mice upon TFP5 treatment," said senior author Dr. Harish C. Pant, senior investigator in neurosciences at the [US] National Institutes of Health. "Therefore, we suggest that TFP5 should be an effective therapeutic compound."

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