Tau kinase inhibitors protect hippocampal synapses despite of insoluble tau accumulation.
A better understanding of the cellular and molecular pathomechanisms of Alzheimer's disease (AD) is a prerequisite for the development of efficient treatments. We have used a novel assay system based on virus-transduced organotypic hippocampal slice cultures that mimics important aspects of tau-driven AD pathology in a short time frame. Human tau P301L, when expressed in pyramidal neurons of hippocampal slice cultures, was increasingly phosphorylated at several disease-relevant epitopes, leading to progressive neuronal dystrophy and formation of RIPA-insoluble tau. AD-like tau hyperphosphorylation was reduced by the tau kinase inhibitors lithium and SRN-003-556, but RIPA-insoluble tau remained unaffected after treatment with any of these substances. Only SRN-003-556 was able to protect hippocampal neurons from synaptic damage that was presumably caused by a toxic soluble tau fraction. These data provide first mechanistic insights towards the functional benefits of SRN-003-556 that have been observed in vivo.
Hinners
Ina
I
KeyNeurotek Pharmaceuticals AG, ZENIT-Technologie Park, Leipziger Strasse 44, D-39120 Magdeburg, Germany. ina.hinners@keyneurotek.de
Hill
Anika
A
Otto
Ulrike
U
Michalsky
Anke
A
Mack
Till G A
TG
Striggow
Frank
F
D000818:Animals; D000831:Animals, Newborn; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005452:Fluoresceins; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology*; D009410:Nerve Degeneration / Q000235:genetics; D016900:Neurofilament Proteins / Q000378:metabolism; D009924:Organ Culture Techniques; D009930:Organic Chemicals / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012694:Serine / Q000378:metabolism; D018709:Statistics, Nonparametric; D013569:Synapses / Q000187:drug effects* / Q000378:metabolism*; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods; D016875:tau Proteins / Q000378:metabolism*
D005452:Fluoresceins; D016900:Neurofilament Proteins; D009930:Organic Chemicals; D047428:Protein Kinase Inhibitors; C435731:fluoro jade; D016875:tau Proteins; D049452:Green Fluorescent Proteins; D012694:Serine