Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction?

Perić, Aleksandar; Annaert, Wim

doi:10.1007/s00401-014-1379-7

Cited by 126 publications

(115 citation statements)

References 178 publications

(283 reference statements)

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“…We and others have proposed that autophagic clearance of proteinopathy in AD would be an ideal alternative target (14,33,34). This notion is substantiated by the autophagy-related pathology found in AD brain evidenced by abnormal acidified lysosomes, accumulated amyloid plaques, and Tau fibrils (49). Furthermore, the down-regulation of PS1 can result in impaired lysosome function, reduced p62 expression, and defective Tau proteostasis (50,51).…”

Section: Discussionmentioning

confidence: 93%

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

Wang

Her

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 93%

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

Wang

Her

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…[178][179][180][181] It is possible that the H1 haplotype is associated with impaired autophagy, or with dysfunction of MAPT, which may lead to autophagy impairment. 26 However, this hypothesis still needs to be supported by future research.…”

Section: Maptmentioning

confidence: 99%

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

2015

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“…Moreover, growing evidence has shown that autophagy is impaired in AD (19)(20)(21). Histological analysis shows accumulation of autophagosomes and autolysosomes in neurons of AD brains (22).…”

mentioning

confidence: 99%

Stimulation of TLR4 Attenuates Alzheimer’s Disease–Related Symptoms and Pathology in Tau-Transgenic Mice

Qin

Liu

Hao

et al. 2016

The Journal of Immunology

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Alzheimer’s disease (AD) is characterized by intracellular neurofibrillary tangles. The primary component, hyperphosphorylated Tau (p-Tau), contributes to neuronal death. Recent studies have shown that autophagy efficiently degrades p-Tau, but the mechanisms modulating autophagy and subsequent p-Tau clearance in AD remain unclear. In our study, we first analyzed the relationship between the inflammatory activation and autophagy in brains derived from aged mice and LPS-injected inflammatory mouse models. We found that inflammatory activation was essential for activation of autophagy in the brain, which was neuronal ATG5-dependent. Next, we found that autophagy in cultured neurons was enhanced by LPS treatment of cocultured macrophages. In further experiments designed to provoke chronic mild stimulation of TLR4 without inducing obvious neuroinflammation, we gave repeated LPS injections (i.p., 0.15 mg/kg, weekly for 3 mo) to transgenic mice overexpressing human Tau mutant (P301S) in neurons. We observed significant enhancement of neuronal autophagy, which was associated with a reduction of cerebral p-Tau proteins and improved cognitive function. In summary, these results show that neuroinflammation promotes neuronal autophagy and that chronic mild TLR4 stimulation attenuates AD-related tauopathy, likely by activating neuronal autophagy. Our study displays the beneficial face of neuroinflammation and suggests a possible role in the treatment of AD patients.

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Early etiology of Alzheimer’s disease: tipping the balance toward autophagy or endosomal dysfunction?

Cited by 126 publications

References 178 publications

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

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

Genetic perspective on the role of the autophagy-lysosome pathway in Parkinson disease

Stimulation of TLR4 Attenuates Alzheimer’s Disease–Related Symptoms and Pathology in Tau-Transgenic Mice

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