title: An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice.
abstract: An orally bioavailable and blood-brain barrier penetrating analog of the kinase inhibitor K252a was able to prevent the typical motor deficits in the tau (P301L) transgenic mouse model (JNPL3) and markedly reduce soluble aggregated hyperphosphorylated tau. However, neurofibrillary tangle counts were not reduced in the successfully treated cohort, suggesting that the main cytotoxic effects of tau are not exerted by neurofibrillary tangles but by lower molecular mass aggregates of tau. Our findings strongly suggest that abnormal tau hyperphosphorylation plays a critical role in the development of tauopathy and suggest a previously undescribed treatment strategy for neurodegenerative diseases involving tau pathology.
authors.affiliation: Sirenade Pharmaceuticals, Am Klopferspitz 19a, 82152 Martinsried, Germany.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Le Corre
authors.forename: Hans W
authors.initials: HW
authors.lastname: Klafki
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Plesnila
authors.forename: Gabriele
authors.initials: G
authors.lastname: Hübinger
authors.forename: Axel
authors.initials: A
authors.lastname: Obermeier
authors.forename: Heidi
authors.initials: H
authors.lastname: Sahagún
authors.forename: Barbara
authors.initials: B
authors.lastname: Monse
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.forename: Jason
authors.initials: J
authors.lastname: Eriksen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Zehr
authors.forename: Mei
authors.initials: M
authors.lastname: Yue
authors.forename: Eileen
authors.initials: E
authors.lastname: McGowan
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Dickson
authors.forename: Michael
authors.initials: M
authors.lastname: Hutton
authors.forename: Hanno M
authors.initials: HM
authors.lastname: Roder
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015394:Molecular Structure; D009043:Motor Activity / Q000502:physiology; D019957:Motor Skills Disorders / Q000503:physiopathology / Q000517:prevention & control*; D019319:Okadaic Acid / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010805:Physical Conditioning, Animal; D051381:Rats; D012995:Solubility; D019076:Transgenes / Q000235:genetics; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*
chemical_list: D002227:Carbazoles; C512359:SRN 003-556; D016875:tau Proteins; D019319:Okadaic Acid