Abstract
Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP+/– mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP+/+ mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP+/– mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.
Footnotes
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This work was supported, in part, by the United States-Israel Binational Science Foundation, by the Neufeld Memorial Award, by the Israel Science Foundation, by Allon Therapeutics Inc., by the Institute for the Study of Aging, and by the Dr. Diana and Zyga Elton Fund.
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This work is in partial fulfillment of the requirements for the Ph.D. degree of I.V.-S.
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I.G. is the incumbent of the Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University and the Director of the Adams Super Center for Brain Studies and the Levie-Adersheim-Gitter fMRI Institute and serves as the chief Scientific Officer of Allon Therapeutics Inc. NAP is in phase II clinical development by Allon Therapeutics Inc.
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I.V.-S. and A.P. contributed equally to this work.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.129551.
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ABBREVIATIONS: ADNP, activity-dependent neuroprotective protein; +/+, wild type; +/–, heterozygous; PCR, polymerase chain reaction; RT, reverse transcription; GSK3β, glycogen synthase kinase-3β; GFAP, glial fibrillary acidic protein.
- Received August 2, 2007.
- Accepted August 23, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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