Death-associated protein kinase 1 has a critical role in aberrant tau protein regulation and function

Abstract

The presence of tangles composed of phosphorylated tau is one of the neuropathological hallmarks of Alzheimer's disease (AD). Tau, a microtubule (MT)-associated protein, accumulates in AD potentially as a result of posttranslational modifications, such as hyperphosphorylation and conformational changes. However, it has not been fully understood how tau accumulation and phosphorylation are deregulated. In the present study, we identified a novel role of death-associated protein kinase 1 (DAPK1) in the regulation of the tau protein. We found that hippocampal DAPK1 expression is markedly increased in the brains of AD patients compared with age-matched normal subjects. DAPK1 overexpression increased tau protein stability and phosphorylation at multiple AD-related sites. In contrast, inhibition of DAPK1 by overexpression of a DAPK1 kinase-deficient mutant or by genetic knockout significantly decreased tau protein stability and abolished its phosphorylation in cell cultures and in mice. Mechanistically, DAPK1-enhanced tau protein stability was mediated by Ser71 phosphorylation of Pin1, a prolyl isomerase known to regulate tau protein stability, phosphorylation, and tau-related pathologies. In addition, inhibition of DAPK1 kinase activity significantly increased the assembly of MTs and accelerated nerve growth factor-mediated neurite outgrowth. Given that DAPK1 has been genetically linked to late onset AD, these results suggest that DAPK1 is a novel regulator of tau protein abundance, and that DAPK1 upregulation might contribute to tau-related pathologies in AD. Therefore, we offer that DAPK1 might be a novel therapeutic target for treating human AD and other tau-related pathologies.

Caffeic acid phenethyl ester (CAPE) protects PC12 cells from MPP+ toxicity by inducing the expression of neuron-typical proteins

“…Images from four fields per well were taken every 24 h of incubation, from 24 h to 192 h. Neurites length, the number of neurites/cell, maximum neurite length, branch points and the percentage of differentiated cells were analyzed in the Image J software (NIH image). Only those cells with at least one neurite with a length equal to (or higher than) the cell body diameter were considered to be differentiated (Das et al, 2004;Kim et al, 2014). Experiments were repeated three times using cell cultures prepared on different days.…”

Pin1 dysregulation helps to explain the inverse association between cancer and Alzheimer's disease

“…In contrast to cancer, Pin1 function is inhibited in human AD by multiple mechanisms, including Pin1 downregulation [48], Pin1 oxidation [41, 49], Pin1 phosphorylation [50] or Pin1 sequestration [51] or even possible Pin1 promoter polymorphisms [52], Pin1 knockout mice develop a syndrome similar to AD characterized by hyper-phosphorylated tau and neurodegeneration [32]. They also display pathogenic processing of APP, leading to Aβ accumulation [43, 53].…”

DAPK1 Mediates LTD by Making CaMKII/GluN2B Binding LTP Specific

“…DAPK1 is a potent mediator of cell death (Bialik and Kimchi, 2013), and it’s activity is accordingly tightly regulated: its kinase activity is suppressed by auto-phosphorylation of S308 within the Ca 2+ /CaM-binding regulatory region and DAPK1 activation requires both dephosphorylation of this site and Ca 2+ /CaM binding (Shohat et al, 2001). Increased neuronal DAPK1 activation has been demonstrated directly only after ischemia (Schumacher et al, 2002; Shamloo et al, 2005; Tu et al, 2010), although protein levels are increased also after ceramide induced stress (Pelled et al, 2002) and in Alzheimer’s disease (Kim et al, 2014; 2016). Additionally, while DAPK1/GluN2B binding is required for ischemic neuronal cell death (Tu et al, 2010), nothing is known about the regulation of DAPK1 binding to GluN2B.…”