AβPP induces cdk5-dependent tau hyperphosphorylation in transgenic mice Tg2576

Abstract

Previous studies of Aβ-induced neuronal damage of hippocampal cells in culture have provided strong evidence that deregulation of the Cdk5/p35 kinase system is involved in the neurodegeneration pathway. Cdk5 inhibitors and antisense probes neuroprotected hippocampal cells against the neurotoxic action of Aβ. To further investigate the mechanisms underlying the participation of Cdk5 in neuronal degeneration, the transgenic mouse containing the Swedish mutations, Tg2576, was used as an animal model. Immunocytochemical studies using anti-Aβ (1−17) antibody evidenced the presence of labeled small-clustered core plaques in the hippocampus and cortex of 18-month-old transgenic mice brains. The loss of granular cells without a compressed appearance was detected in the vicinity of the cores in the dentate gyrus of the hippocampus. Immunostaining of Tg2576 brain sections with antibodies AT8, PHF1 and GFAP labeled punctuate dystrophic neurites in and around the amyloid core. Reactive astrogliosis around the plaques in the hippocampus was also observed. Studies at the molecular level showed differences in the expression of the truncated Cdk5 activator p25 in the transgenic animal, as compared with wild type controls. However no differences in Cdk5 levels were detected, thus corroborating previous cellular findings. Interestingly, hyperphosphorylated tau epitopes were substantially increased as assessed with the AT8 and PHF1 antibodies, in agreement with the observation of a p25 increase in the transgenic animal. These observations strongly suggest that the increased exposure of Alzheimer's type tau phosphoepitopes in the transgenic mice correlated with deregulation of Cdk5 leading to an increase in p25 levels. These studies also provide further evidence on the links between extraneuronal amyloid deposition and tau pathology.

Suppression of Cyclin-Dependent Kinase 5 Activation by Amyloid Precursor Protein: A Novel Excitoprotective Mechanism Involving Modulation of Tau Phosphorylation

“…Calpain/p25/CDK5 is a major determinant in excitotoxicity Our findings, along with others, indicate that CDK5 is one of the key mediators regulating both amyloidogenesis and formation of tau/NFTs (Otth et al, 2002;Town et al, 2002;Lee and Tsai, 2003). Therefore, we studied the role of CDK5 in neuronal cell death in the context of excitotoxicity.…”

Normalizing the gene dosage of Dyrk1A in a mouse model of Down syndrome rescues several Alzheimer's disease phenotypes

“…An association between Aβ and hyperphosphorylated tau has been shown (Ribe et al, 2005;Oddo et al, 2003). Soluble Aβ can induce inactivation of phosphatases (Vogelsberg-Ragaglia et al, 2001) and activation of tau kinases (Hoshi et al, 2003;Otth et al, 2002), and promoting tau phosphorylation (Hoshi et al, 2003;Otth et al, 2002;Zheng et al, 2002) and the direct interaction between tau and Aβ induces tau aggregation and hyperphosphorylation (Rank et al, 2002). In addition, tau seems to be required for the neurotoxic effects of Aβ oligomers (Shipton et al, 2011).…”

Induction of Dickkopf-1, a Negative Modulator of the Wnt Pathway, Is Associated with Neuronal Degeneration in Alzheimer's Brain

“…We wondered whether a p53 transcription program is involved in the formation of NFTs in ␤AP-treated neurons. Formation of NFTs results from a hyperphosphorylation of the tau protein, which is potentially driven by glycogen-synthase kinase-3␤ (GSK3␤) (Takashima et al, 1998;Otth et al, 2002), an enzyme that is under the control of the canonical Wnt signaling pathway (Grimes and Jope, 2001). This pathway is activated by different Wnt secreted glycoproteins that interact with the Frizzled and LRP5/6 (LDL receptor-related protein type 5 and 6) membrane coreceptors (Dale, 1998).…”