An inhibitor of tau hyperphosphorylation prevents severe motor impairments in tau transgenic mice.
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.
Le Corre
Sylvie
S
Sirenade Pharmaceuticals, Am Klopferspitz 19a, 82152 Martinsried, Germany.
Klafki
Hans W
HW
Plesnila
Nikolaus
N
Hübinger
Gabriele
G
Obermeier
Axel
A
Sahagún
Heidi
H
Monse
Barbara
B
Seneci
Pierfausto
P
Lewis
Jada
J
Eriksen
Jason
J
Zehr
Cynthia
C
Yue
Mei
M
McGowan
Eileen
E
Dickson
Dennis W
DW
Hutton
Michael
M
Roder
Hanno M
HM
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*
D002227:Carbazoles; C512359:SRN 003-556; D016875:tau Proteins; D019319:Okadaic Acid