Insulin Dysfunction InducesIn VivoTau Hyperphosphorylation through Distinct Mechanisms

Abstract

Hyperphosphorylated tau is the major component of paired helical filaments in neurofibrillary tangles found in Alzheimer's disease (AD) brains, and tau hyperphosphorylation is thought to be a critical event in the pathogenesis of the disease. The large majority of AD cases is late onset and sporadic in origin, with aging as the most important risk factor. Insulin resistance, impaired glucose tolerance, and diabetes mellitus (DM) are other common syndromes in the elderly also strongly age dependent, and there is evidence supporting a link between insulin dysfunction and AD. To investigate the possibility that insulin dysfunction might promote tau pathology, we induced insulin deficiency and caused DM in mice with streptozotocin (STZ). A mild hyperphosphorylation of tau could be detected 10, 20, and 30 d after STZ injection, and a massive hyperphosphorylation of tau was observed after 40 d. The robust hyperphosphorylation of tau was localized in the axons and neuropil, and prevented tau binding to microtubules. Neither mild nor massive tau phosphorylation induced tau aggregation. Body temperature of the STZ-treated mice did not differ from control animals during 30 d, but dropped significantly thereafter. No change in ␤-amyloid (A␤) precursor protein (APP), APP C-terminal fragments, or A␤ levels were observed in STZ-treated mice; however, cellular protein phosphatase 2A activity was significantly decreased. Together, these data indicate that insulin dysfunction induced abnormal tau hyperphosphorylation through two distinct mechanisms: one was consequent to hypothermia; the other was temperature-independent, inherent to insulin depletion, and probably caused by inhibition of phosphatase activity.

Short-Term High-Fat-and-Fructose Feeding Produces Insulin Signaling Alterations Accompanied by Neurite and Synaptic Reduction and Astroglial Activation in the Rat Hippocampus

“…Tau phosphorylation sites have been extensively studied in terms of the impairment for microtubule binding and the formation of insoluble neurofibrillary tangles that cause multiple anomalies, from axonal dysfunction to the loss of neuronal integrity and neuronal death. [24][25][26]35 Finally, we examined whether the biochemical, morphologic, and structural changes found in the hippocampus of HFFD rats were accompanied by reactive astrocyte activation. One of the pathologic features of obesity and InsRes is inflammation, and it has been described that central inflammation has an impact on brain function possibly through the import of inflammatory cytokines and immune cells into the central nervous system.…”

“…[21][22][23] It has also been proposed that insulin can modify microtubule stabilization through inhibition of glycogen synthase kinase 3b (GSK3b), a kinase that can phosphorylate the microtubule-associated protein (MAP) tau. 24,25 Given these crucial roles of insulin in the hippocampus, it could be speculated that systemic insulin alterations resulting from obesity and InsRes could result in hippocampal insulin alterations that underlie cognitive impairment. In this regard, it has been reported that long-term high-fat (not fructose) feeding in mice produced alterations in Akt and GSK3b signaling in the hippocampus.…”

Biochemistry and Cell Biology of Tau Protein in Neurofibrillary Degeneration

“…Other cellular targets should sense the change in biochemical potential in a similar fashion, and in fact this has been demonstrated, for example, for neurofilaments (Ishihara et al 2001). An overall shift of phosphorylation potential can occur, for example, by a temperature drop during anesthesia or experimental diabetes, which reduces the activity of PP2a and thus mimics an Alzheimer-like phosphorylation state on Tau, reminiscent of the effects of aging (Planel et al 2007a;Planel et al 2007b;Veeranna et al 2009). Conversely, heat stress and oxidative stress activate PP2a and thus generate a low state of Tau phoshorylation, which protects against DNA damage (Davis et al 1997;Sultan et al 2011).…”

Is Insulin Resistant Brain State a Central Feature of the Metabolic-Cognitive Syndrome?

“…Recently, in a mice experimental model, two distinct mechanisms were hypothesized to explain the role of impaired insulin signaling in tau hyperphosphorylation [52]. One, inherent to insulin depletion, probably causes inhibition of the PI3K/Akt pathway, in particular by inhibition of protein phosphatase 2 (PP2A) activity and increasing activation of GSK-3β [53].…”

“…The other mechanism was consequent to hypothermia. In fact, deficits in peripheral glucose/energy metabolism lead to relative hypothermia, with direct inhibition of PP2A activity, finally resulting in hyperphosphorylation of tau [52], which cannot be transported into axons, and that then accumulates and aggregates in neuronal perikarya [56]. This contributes to neurodegeneration by enhancing oxidative stress and triggering pathophysiological cascades that lead to increased apoptosis destabilizing the microtubule network and other cellular functions [57].…”