Hyperphosphorylation of Tau Induced by Naturally Secreted Amyloid-β at Nanomolar Concentrations Is Modulated by Insulin-dependent Akt-GSK3β Signaling Pathway

Abstract

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.

Insulin signalling in Alzheimer′s disease and diabetes: from epidemiology to molecular links

“…These two central observations suggest that insulin signalling impacts on at least two parts of the proposed canonical amyloid cascade pathway of AD and evidence from in vitro studies, supporting such a suggestion, find that insulin protects neurons from Ab-induced phenotypes [21,22]. One remarkable observation from experimental studies in rodents, however, is that this cascade initiated by Ab oligomers and resulting in tau phosphorylation and aggregation does not occur in vivo.…”

“…Insulin decreases tau phosphorylation via inhibition of GSK3 [18,19] Insulin alters APP proteolytic cleavage [20] Insulin protects neurons against Ab toxicity [21,22] Insulin regulates IDE expression; mice lacking IDE have decreased rates of insulin and Ab degradation, exhibit brain Ab accumulation and develop hyperinsulinaemia [59] Ab modulates IIS in the brain by binding to IRs and disrupting signalling capacity leading to reduced surface expression of IRs and promotion of synaptic loss [63,64] Upregulation of IIS genes in a mouse model of amyloidosis as a possible means for neuroprotection [23] Lack of IRS2 is associated with increased tau phosphorylation and cognitive impairment [24,25] In vitro and in vivo evidence…”

The herbal compound geniposide rescues formaldehyde-induced apoptosis in N2a neuroblastoma cells

“…More specifically, levels of Akt and phospho-Akt, as well as Akt activity, were all reported to be decreased relative to controls [31]. Furthermore, the Akt signaling pathway has been shown to modulate the hyperphosphorylation of tau induced by nanomolar concentrations of naturally secreted amyloid-β [32], although hyperphosphorylation of tau can be promoted by many additional factors [33]. We found that GP up-regulates Akt and Bcl2, and down-regulates FOXO3 and P53.…”

Hyperphosphorylation of Tau Protein in Down ’s Dementia and Alzheimer’s Disease: Methylation and Implications in Prevention and Therapy

“…Treating cells with the insulin-sensitizing drug rosiglitazone attenuated the Aβ-dependent hyperphosphorylation of Tau [39].…”