Hyperphosphorylation of Tau induced by naturally secreted amyloid-β at nanomolar concentrations is modulated by insulin-dependent Akt-GSK3β signaling pathway.
Alzheimer disease (AD) is neuropathologically characterized by the formation of senile plaques from amyloid-β (Aβ) and neurofibrillary tangles composed of phosphorylated Tau. Although there is growing evidence for the pathogenic role of soluble Aβ species in AD, the major question of how Aβ induces hyperphosphorylation of Tau remains unanswered. To address this question, we here developed a novel cell coculture system to assess the effect of extracellular Aβ at physiologically relevant levels naturally secreted from donor cells on the phosphorylation of Tau in recipient cells. Using this assay, we demonstrated that physiologically relevant levels of secreted Aβ are sufficient to cause hyperphosphorylation of Tau in recipient N2a cells expressing human Tau and in primary culture neurons. This hyperphosphorylation of Tau is inhibited by blocking Aβ production in donor cells. The expression of familial AD-linked PSEN1 mutants and APP ΔE693 mutant that induce the production of oligomeric Aβ in donor cells results in a similar hyperphosphorylation of Tau in recipient cells. The mechanism underlying the Aβ-induced Tau hyperphosphorylation is mediated by the impaired insulin signal transduction because we demonstrated that the phosphorylation of Akt and GSK3β upon insulin stimulation is less activated under this condition. Treating cells with the insulin-sensitizing drug rosiglitazone, a peroxisome proliferator-activated receptor γ agonist, attenuates the Aβ-dependent hyperphosphorylation of Tau. These findings suggest that the disturbed insulin signaling cascade may be implicated in the pathways through which soluble Aβ induces Tau phosphorylation and further support the notion that correcting insulin signal dysregulation in AD may offer a potential therapeutic approach.
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Takayoshi
T
Tokutake
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Kensaku
K
Kasuga
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Ryuji
R
Yajima
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Yumi
Y
Sekine
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Toshiyuki
T
Tezuka
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Masatoyo
M
Nishizawa
Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan; Center for Transdisciplinary Research, Niigata University, Niigata 951-8585, Japan. Electronic address: ikeuchi@bri.niigata-u.ac.jp.
Takeshi
T
Ikeuchi
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D000077154:Rosiglitazone; D017384:Sequence Deletion; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D007328:Insulin; C054369:MAPT protein, human; C489131:Mapt protein, rat; D047495:PPAR gamma; C508853:PSEN1 protein, human; D053764:Presenilin-1; D045162:Thiazolidinediones; D016875:tau Proteins; D000077154:Rosiglitazone; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases