PDK1 decreases TACE-mediated α-secretase activity and promotes disease progression in prion and Alzheimer's diseases

Abstract

α-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-β (Aβ) peptides, and α-cleavage of cellular prion protein (PrP(C)) prevents its conversion into misfolded, pathogenic prions (PrP(Sc)). The mechanisms leading to decreased α-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-α-converting enzyme (TACE)-mediated α-secretase activity is impaired at the surface of neurons infected with PrP(Sc) or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by Aβ deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-1-mediated internalization of TACE. This dysregulation of TACE increases PrP(Sc) and Aβ accumulation and reduces shedding of TNF-α receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent α-secretase activity and cleavage of APP, PrP(C) and TNFR1, and attenuates PrP(Sc)- and Aβ-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrP(Sc) infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.

Parallel age-associated changes in brain and plasma neuronal pentraxin receptor levels in a transgenic APP/PS1 rat model of Alzheimer's disease

“…Previous work in hippocampal neurons cultured from Tg2576 mice suggests that Aβ accumulation increases phosphoinositide-dependent kinase-1 (PDK-1) activity and decreases TACE activity via Thr735 phosphorylation (Pietri et al, 2013). Other reports indicate that inactive TACE is maintained in a dimeric state (Xu et al, 2012).…”

“…those with the most advanced Aβ pathology), which demonstrated higher expression of membrane-associated NPR than age-matched Wt animals. This result may be mechanistically related to Aβ-related TACE inactivation (Pietri et al, 2013), since TACE-mediated cleavage of NPR is required for its release from the plasma membrane (Cho et al, 2008). TACE dimers in the cell membrane represent inactive TACE (Xu et al, 2012), and at older ages, Tg rats exhibit higher levels of phospho-TACE dimers than Wt rats.…”

PDK1: A signaling hub for cell migration and tumor invasion

“…Afterwards, PDK1 has been found involved in other different physiological processes including development [27], blood vessel formation [28], and neuron differentiation [113]. Moreover, alterations of PDK1 functions have also a relevant role in pathology such as Alzheimer's disease [114], diabetes [115] and cancer [20,102].…”

Taking advantage of physiological proteolytic processing of the prion protein for a therapeutic perspective in prion and Alzheimer diseases

“…13,26,27 This decrease is mediated by an increased activity of 3-phosphoinositide-dependent kinase-1 (PDK1) in prion-infected neurons, and siRNA-mediated silencing of PDK1 delays mortality in prion-infected mice. 28 Also, the annual incidence of prion diseases is approximately 1 in 1 000 000 persons. 29 Thus, these disorders are among the most rare neurodegeneratives diseases, and physiological proteolytic cleavages of PrP C may in part explain this very low incidence rate.…”