Amyloid‐β‐induced toxicity of primary neurons is dependent upon differentiation‐associated increases in tau and cyclin‐dependent kinase 5 expression

Abstract

It has previously been reported that amyloid-b (Ab) peptide is neurotrophic to undifferentiated but neurotoxic to differentiated primary neurons. The underlying reasons for this differential effect is not understood. Recently, the toxicity of Ab to neurons was shown to be dependent upon the activation of cyclindependent kinase 5 (Cdk5), thought to promote tau phosphorylation that leads to cytoskeletal disruption, morphological degeneration and apoptosis. Here we report that Cdk5, tau, and phosphorylated-tau (P-tau) are expressed at very low levels in undifferentiated primary neurons, but that the expression of Cdk5 and tau and the phosphorylation of tau increase markedly between 4 and 8 days of differentiation in vitro. Tau expression decreased after this time, as did the level of P-tau, to low levels by 17 days. Ab induced tau phosphorylation of neurons only after ‡ 4 days of differentiation, a time that coincides with the onset of Ab toxicity. Blocking tau expression (and therefore tau phosphorylation) with an antisense oligonucleotide completely blocked Ab toxicity of differentiated primary neurons, thereby confirming that tau was essential for mediating Ab toxicity. Our results demonstrate that differentiation-associated changes in tau and Cdk-5 modulate the toxicity of Ab and explain the opposite responses of differentiated and undifferentiated neurons to Ab. Our results predict that only cells containing appreciable levels of tau are susceptible to Ab-induced toxicity and may explain why Ab is more toxic to neurons compared with other cell types.

Enduring Elevations of Hippocampal Amyloid Precursor Protein and Iron Are Features of β-Amyloid Toxicity and Are Mediated by Tau

“…Aβ injection also resulted in the striking hyperphosphorylation of the remaining tau at Ser396 (Fig. 9a, c; +135 %, p=0.002, 2-tailed t test), a site linked with AD pathology, confirming a response to Aβ challenge that has been previously reported [1,23,32]. An attenuated (but significantly) decrease in tau was observed in 12-month-old WT mice injected with Aβ ( Fig.…”

“…Proponents of the amyloid cascade hypothesis posit that Aβ recruits tau protein as a downstream effector of toxicity. Aβ-induced cytotoxicity was shown to be tau-dependent in primary neuronal culture: the neurons are protected when tau is lowered by either genetic ablation [knockout (KO)], or by leaving them undifferentiated (where they express lower tau levels than differentiated neurons) [1,2]. Ex vivo studies of tau KO neurons revealed that the Aβ-induced axonal transport deficits and impairment of hippocampal long-term potentiation were mediated by tau [3,4].…”

Role of Cyclin-Dependent Kinase 5 in the Neurodegenerative Process Triggered by Amyloid-Beta and Prion Peptides: Implications for Alzheimer’s Disease and Prion-Related Encephalopathies

“…Since this decrease was only partial, we can speculate that there are other cell death pathways acting simultaneously and independently from Cdk5, and thus not inhibited by roscovitine (Agostinho et al 2003;Ferreiro et al 2006). Although several other studies have shown that Cdk5 mediates the neurotoxicity triggered by Abpeptides (Alvarez et al 2001;Liu et al 2004), this is the first study showing that Cdk5 is in part responsible for the neurotoxic effect of PrP. In our experimental conditions, PrP 106-126 and Ab 1-40 did not affect Cdk5 levels (Fig.…”

Biometals and Their Therapeutic Implications in Alzheimer's Disease

“…Interestingly, Aβ-induced cytotoxicity was shown to be tau-dependent in primary neuronal culture with either genetic depletion of tau, or using an undifferentiated neuronal culture (which has a lower tau level than differentiated neurons) [56,57]. Tau knockout studies revealed that the Aβ-induced axonal transport deficits and impairment of hippocampal LTP were mediated by tau [58,59].…”