ErbB2 regulates autophagic flux to modulate the proteostasis of APP-CTFs in Alzheimer’s disease

Abstract

Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer's disease (AD). An RNA interference screen using APP-CTF [99-residue CTF (C99)]-and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34-Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.ErbB2 | Alzheimer's disease | Aβ | C99 | autophagy A myloid plaques are the primary cause of neurodegeneration in the brains of patients with Alzheimer's disease (AD) (1). Amyloid plaques are composed of amyloid-β (Aβ) peptides that are produced by stepwise cleavages of amyloid precursor protein (APP) by β-and γ-secretase (2). Therapeutic approaches toward treatment of AD developed in the past decade have centered on the prevention of Aβ production (3). The majority of these studies focused on either the augmentation of α-secretase activity, which can reduce the production of Aβ, or the inhibition of β-/γ-secretase activities (4). Unfortunately, the nonselective inhibition of β-secretase and γ-secretase results in unavoidable side effects due to the interference of other physiological substrates of β-secretase and γ-secretase (5, 6).ErbB2 is a member of the epidermal growth factor receptor (EGFR)/ErbB family [which consists of four closely related receptor tyrosine kinases (ErbB1-4, also known as HER1-4)] and is tightly associated with neuritic plaques in AD (7). The correlation between EGFR/ErbB signaling and AD pathogenesis has been well documented in various studies (8-10). Ras GTPase activation mediates EGF-induced stimulation of γ-secretase to increase the nuclear function of the APP intracellular domain (AICD) (11). Consistent with the role of EGF signaling in AD, the intracellular mediators downstream of EGF signaling (which include Grb2, ShcA, and Abl) directly or indirectly interact with APP (12); these findings support the correlation between EGFR/ ErbB-dependent signaling and AD susceptibility.Autophagy controls the clearance of misfolded proteins and damaged organelles, and plays an essential role in maintaining neuronal functions (13,14). Previous studies have demonstrated that autophagy is instrumental to the clearance of proteins related to neurodegenerative diseases; these proteins include polyg...

Nicotinate‐curcumin ameliorates cognitive impairment in diabetic rats by rescuing autophagic flux in CA1 hippocampus

“…Given that autophagic flux dysfunction in the hippocampus may contribute to neurodegenerative diseases, improving autophagic flux in these areas is hence considered as a potential therapeutic approach to cognitive decline. 31,32 In the present study, we found that NC restored autophagic flux in hippocampus CA1 region of DM rats.…”

The Proteasomal Deubiquitinating Enzyme PSMD14 Regulates Macroautophagy by Controlling Golgi-to-ER Retrograde Transport

“…In general, several studies have shown that the inhibition of the 20S catalytic core with the use of blockers of the β-subunits triggers the enhancement of the biogenesis of LC3B-positive autophagosomes [67][68][69][70][71][72]. In this regard, we showed that MG132 caused an increment of the LC3II/LC3I ratio and a significant decrease in full-length endogenous APP levels, strongly indicating a reduction in APP by macroautophagy [38,[73][74][75][76]. Here, we show that blockage of the PSMD14 DUB activity, a component of the 19S RP, plays a negative role in the biogenesis of LC3B-positive autophagosomes, given new insights about the control of macroautophagy.…”

Interplay Between the Autophagy-Lysosomal Pathway and the Ubiquitin-Proteasome System: A Target for Therapeutic Development in Alzheimer’s Disease

“…Moreover, in N2a neuronal cells TFEB-overexpression caused accelerated lysosomal degradation of APP/CTFs through endocytosis (Xiao et al, 2015 ). Furthermore, the involvement of the PI3K-III complex has been reported in the sorting of APP from the cell surface to endolysosomal and autophagic compartments (Swaminathan et al, 2016 ) and in the autophagic-lysosomal degradation of APP-CTFs in AD animal models (Wang et al, 2017 ; Yang et al, 2017 ). Altogether, APP-CTFs—but more importantly CTFβ—emerges as an important pathogenic factor for AD and as a potential biomarker in cerebrospinal fluid of AD patients (García-Ayllón et al, 2017 ).…”