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Promising Compound Restores Memory Loss and Reverses Symptoms of Alzheimer's in Mice
SandyHalperin
Posted: Thursday, January 3, 2013 7:05 AM
Joined: 4/29/2012
Posts: 76


I received this news today from someone on LinkedIn: http://www.sciencedaily.com/releases/2013/01/130102140535.htm

Any comments - thoughts?

Thanks,

Sandy


organicgreendoctor
Posted: Thursday, January 3, 2013 9:28 AM
Joined: 10/28/2012
Posts: 33


of mice and men

since ive been diagnosed 2 years ago ive seen a lot of these articles

on promising treatments

most if not all dont turn out to work in humans 

but one day one of them will progress to human trials 

and show to be effective

maybe its this one 

time will tell

the organicgreen doctor

www.organicgreendoctor.com


onward
Posted: Thursday, January 3, 2013 10:02 AM
Joined: 12/20/2011
Posts: 217


 

 

Thanks for posting, Sandy.

 

Sounds very promising - though as organicgreendoctor noted, we'll just have to wait and see.

 

In case anyone's interested, I think this is the abstract from the scientific paper.  Maybe Lane or someone else here can decipher it.

A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice

 

 

  1. 1Correspondence: National Institute of Neurological Disorders and Stroke, National Institutes of Health, 49 Convent Dr., MSC 4479, Bldg. 49, Rm. 2A28, Bethesda, MD 20892, USA. E-mail: panth@ninds.nih.gov

Abstract

Alzheimer's disease (AD), one of the leading neurodegenerative disorders of older adults, which causes major socioeconomic burdens globally, lacks effective therapeutics without significant side effects. Besides the hallmark pathology of amyloid plaques and neurofibrillary tangles (NFTs), it has been reported that cyclin-dependent kinase 5 (Cdk5), a critical neuronal kinase, is hyperactivated in AD brains and is, in part, responsible for the above pathology. Here we show that a modified truncated 24-aa peptide (TFP5), derived from the Cdk5 activator p35, penetrates the blood-brain barrier after intraperitoneal injections, inhibits abnormal Cdk5 hyperactivity, and significantly rescues AD pathology (up to 70–80%) in 5XFAD AD model mice. The mutant mice, injected with TFP5 exhibit behavioral rescue, whereas no rescue was observed in mutant mice injected with either saline or scrambled peptide. However, TFP5 does not inhibit cell cycle Cdks or normal Cdk5/p35 activity, and thereby has no toxic side effects (even at 200 mg/kg), a common problem in most current therapeutics for AD. In addition, treated mice displayed decreased inflammation, amyloid plaques, NFTs, cell death, and an extended life by 2 mo. These results suggest TFP5 as a potential therapeutic, toxicity-free candidate for AD.—Shukla, V., Zheng, Y.-L., Mishra, S. K., Amin, N. D., Steiner, J., Grant, P., Kesavapany, S., Pant, H. C. A truncated peptide from p35, a Cdk5 activator, prevents Alzheimer's disease phenotypes in model mice.

 

http://www.fasebj.org/content/27/1/174.abstract


Lane Simonian
Posted: Thursday, January 3, 2013 11:36 AM
Joined: 12/12/2011
Posts: 4855


Here is a similar abstract, which reinforces the one Onward posted. 

 

The aberrant hyperactivation of Cyclin-dependent kinase 5 (Cdk5), by the production of its truncated activator p25, results in the formation of hyperphosphorylated tau, neuroinflammation, amyloid deposition, and neuronal death in vitro and in vivo. Mechanistically, this occurs as a result of a neurotoxic insult that invokes the intracellular elevation of calcium to activate calpain, which cleaves the Cdk5 activator p35 into p25. It has been shown previously that the p25 transgenic mouse as a model to investigate the mechanistic implications of p25 production in the brain, which recapitulates deregulated Cdk5-mediated neuropathological changes, such as hyperphosphorylated tau and neuronal death. To date, strategies to inhibit Cdk5 activity have not been successful in targeting selectively aberrant activity without affecting normal Cdk5 activity. Here we show that the selective inhibition of p25/Cdk5 hyperactivation in vivo, through overexpression of the Cdk5 inhibitory peptide (CIP), rescues against the neurodegenerative pathologies caused by p25/Cdk5 hyperactivation without affecting normal neurodevelopment afforded by normal p35/Cdk5 activity. Tau and amyloid pathologies as well as neuroinflammation are significantly reduced in the CIP–p25 tetra transgenic mice, whereas brain atrophy and subsequent cognitive decline are reversed in these mice. The findings reported here represent an important breakthrough in elucidating approaches to selectively inhibit the p25/Cdk5 hyperactivation as a potential therapeutic target to reduce neurodegeneration.

 

http://www.jneurosci.org/content/33/1/334.abstract 

 

 

A scientist recently referred me to the KEGG pathway for Alzheimer's disease. The important part of the chart is the bottom.  The only thing missing on the bottom is an arrow from Cdk5/p25 to peroxynitrites 

(ONOO-) to GSK3 to tau hyperphosphorylation/neurofibrillary tangles.  The compound in question inhibits the dysregulation of CDK5 which via MAPK contributes to the formation of peroxynitrites.  Thus, the compound could slow down the progression of Alzheimer's disease by limiting the formation of peroxynitrites 

 

http://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2010.06687.x/abstract 

http://www.ncbi.nlm.nih.gov/pubmed/18289732