TY - JOUR
T1 - Novel tubulin and tau neuroprotective fragments sharing structural similarities with the drug candidate NAP (Davuentide)
AU - Gozes, Illana
AU - Iram, Tal
AU - Maryanovsky, Evgenia
AU - Arviv, Carmit
AU - Rozenberg, Liora
AU - Schirer, Yulie
AU - Giladi, Eliezer
AU - Furman-Assaf, Sharon
N1 - Professor Gozes’ laboratory is supported by the AMN Foundation, CFTAU Montreal Circle of Friends and the Adams family, Adams Super Center for Brain Studies, and the Lily and Avraham Gildor Chair for the Investigation of Growth Factors at Tel Aviv University. Initial studies in this research were also partially supported by Allon Therapeutics Inc., Joe and Grace Alter, Barbara and Don Seal and the Oberfeld family. Evgenia Maryanovsky, Carmit Arviv, Liora Rozenberg, and Yulie Schirer performed this work as part of their graduate studies in the Dr. Miriam and Sheldon G. Adelson Graduate School of Medicine associated with the Sackler Faculty of Medicine at Tel Aviv University, while Tal Iram was an undergraduate student at the Sagol School of Neuroscience, Tel Aviv University. We thank Prof. Jada Lewis for her help with the Tau-Tg mice. All peptides are under patent protection, Ramot at Tel Aviv University. Professor Gozes is currently a Humboldt Award Recipient and a fellow at the Hanse- Wissenschftenkolleg, Germany
PY - 2014/5/27
Y1 - 2014/5/27
N2 - NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest.
AB - NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection and reduce tau pathology. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT) and STPTAIPQ were derived from tubulin, and TAPVPMPD (TAP) was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the amyloid-β 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia transgenic mouse model (Tau-Tg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in frontotemporal dementia, novel NAP derivatives that reduce tauopathy and provide neuroprotection are of basic and clinical interest.
KW - Activity-dependent neuroprotective protein (ADNP)
KW - NAP (davunetide)
KW - aggregation
KW - microtubules
KW - neuroprotection
KW - peptides
KW - tau
KW - tauopathy
KW - tubulin
UR - http://www.scopus.com/inward/record.url?scp=84901764370&partnerID=8YFLogxK
U2 - https://doi.org/10.3233/JAD-131664
DO - https://doi.org/10.3233/JAD-131664
M3 - مقالة
C2 - 24503616
SN - 1387-2877
VL - 40
SP - S23-S36
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - S1
ER -