Kidins220 accumulates with tau in human Alzheimer's disease and related models: modulation of its calpain-processing by GSK3β/PP1 imbalance

Abstract

Failures in neurotrophic support and signalling play key roles in Alzheimer's disease (AD) pathogenesis. We previously demonstrated that downregulation of the neurotrophin effector Kinase D interacting substrate (Kidins220) by excitotoxicity and cerebral ischaemia contributed to neuronal death. This downregulation, triggered through overactivation of N-methyl-D-aspartate receptors (NMDARs), involved proteolysis of Kidins220 by calpain and transcriptional inhibition. As excitotoxicity is at the basis of AD aetiology, we hypothesized that Kidins220 might also be downregulated in this disease. Unexpectedly, Kidins220 is augmented in necropsies from AD patients where it accumulates with hyperphosphorylated tau. This increase correlates with enhanced Kidins220 resistance to calpain processing but no higher gene transcription. Using AD brain necropsies, glycogen synthase kinase 3-β (GSK3β)-transgenic mice and cell models of AD-related neurodegeneration, we show that GSK3β phosphorylation decreases Kidins220 susceptibility to calpain proteolysis, while protein phosphatase 1 (PP1) action has the opposite effect. As altered activities of GSK3β and phosphatases are involved in tau aggregation and constitute hallmarks in AD, a GSK3β/PP1 imbalance may also contribute to Kidins220 decreased clearance, accumulation and hampered neurotrophin signalling from early stages of the disease pathogenesis. These results encourage searches for mutations in Kidins220 gene and their possible associations to dementias. Finally, our data support a model where the effects of excitotoxicity drastically differ when occurring in cerebral ischaemia versus progressively sustained toxicity along AD progression. The striking differences in Kidins220 stability resulting from chronic versus acute brain damage may also have important implications for the therapeutic intervention of neurodegenerative disorders.

Functions of the multi‐interacting protein KIDINS220/ARMS in cancer and other pathologies

“…TAU is a microtubule‐associated protein which is hyperphosphorylated in AD . Necropsies from AD patients with different progression stages showed that KIDINS220 expression levels are increased in human brain owing to the increased resistance to calpain cleavage associated with a hyperphosphorylation of KIDINS220 . Potential mechanisms of the involvement of KIDINS220 in the AD have been suggested elsewhere .…”

“…Unlike its reduction in cerebral ischemia, KIDINS220 has shown an enhanced expression in Alzheimer's disease (AD) where it correlates with TAU . TAU is a microtubule‐associated protein which is hyperphosphorylated in AD .…”

“…Unlike its reduction in cerebral ischemia, KIDINS220 has shown an enhanced expression in Alzheimer's disease (AD) where it correlates with TAU. 37 TAU is a microtubule-associated protein which is hyperphosphorylated in AD. 38,39 Necropsies from AD patients with different progression stages showed that KIDINS220 expression levels are increased in human brain owing to the increased resistance to calpain cleavage associated with a hyperphosphorylation of KIDINS220.…”

The entorhinal cortex and neurotrophin signaling in Alzheimer’s disease and other disorders

“…In 1981, loss of trophic support was proposed to be a cause of neurodegenerative diseases such as AD (Appel 1981), but when levels of neurotrophins were measured, they were not necessarily altered in AD, leading to the hypothesis that altered neurotrophin processing and signaling are also important, not necessarily neurotrophin levels (Allen et al, 2011). Recent data suggested that a neurotrophin-related scaffold protein, ARMS/Kidins220 (described further below), contributes to AD (Lopez-Menendez et al, 2013). This protein is a key substrate of neurotrophin signaling and mediates multiple interactions with the cytoskeleton, small GTPases and MAP kinase signaling (Arevalo et al, 2004; Hirata et al, 2007; Higuero et al, 2010; Neubrand et al, 2010; 2012).…”

“…For example, ARMS/Kidins220 could contribute to excitotoxicity by facilitating the activation of NMDA receptors, and this has been suggested to be relevant to AD (Lopez-Menendez et al, 2013). The levels of ARMS/Kidins220 also regulate the trafficking and insertion of GluR1 at synapses.…”