Presenilin-1 Regulates the Expression of p62 to Govern p62-dependent Tau Degradation

Tung, Ying Tsen; Wang, Bo Jeng; Hsu, Wen Ming; Hu, Ming; Her, Guor Mour; Huang, Wei Pang; Liao, Yung Feng

doi:10.1007/s12035-013-8482-y

Cited by 11 publications

(7 citation statements)

References 76 publications

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“…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). On the other hand, dysfunction of autophagy elicited by decreased Beclin-1 expression leads to increased levels of intraneuronal and extracellular Aβ in an AD mouse model (52), whereas induction of autophagy by rapamycin can reduce Aβ42 accumulation, Tau hyperphosphorylation, and oxidative stress to ameliorate cognitive impairment in AD transgenic mice (53).…”

Section: Discussionmentioning

confidence: 96%

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: 96%

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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“…Interestingly, Tung et al found that non-neuronal and neuronal cells lacking PS-1 displayed reduced levels of p62 protein which serves as a “cargo receptor” for tau degradation. Their study suggests a novel mechanism by which the reduction PS-1 or its mutation in FAD impairs p62-dependent tau clearance (Tung et al, 2014 ).…”

Section: Autophagic Impairments In Ad and T2dmmentioning

confidence: 99%

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

2018

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Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.

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“…Associated with the substrate cleavage, their knockdown was found exhibiting inefficiency in the clearance of protein aggregates. Cells deficient in PS1 was found having reduced levels of cargo shuttle protein p62, associated with the degradation of abnormal tau (Tung et al, 2014 ; Caccamo et al, 2017 ).…”

Section: Therapeutic Approaches To Combat Admentioning

confidence: 99%

Perspective Insights into Disease Progression, Diagnostics, and Therapeutic Approaches in Alzheimer's Disease: A Judicious Update

Jan

Azam

Rahman

et al. 2017

Front. Aging Neurosci.

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Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive accumulation of β-amyloid fibrils and abnormal tau proteins in and outside of neurons. Representing a common form of dementia, aggravation of AD with age increases the morbidity rate among the elderly. Although, mutations in the ApoE4 act as potent risk factors for sporadic AD, familial AD arises through malfunctioning of APP, PSEN-1, and−2 genes. AD progresses through accumulation of amyloid plaques (Aβ) and neurofibrillary tangles (NFTs) in brain, which interfere with neuronal communication. Cellular stress that arises through mitochondrial dysfunction, endoplasmic reticulum malfunction, and autophagy contributes significantly to the pathogenesis of AD. With high accuracy in disease diagnostics, Aβ deposition and phosphorylated tau (p-tau) are useful core biomarkers in the cerebrospinal fluid (CSF) of AD patients. Although five drugs are approved for treatment in AD, their failures in achieving complete disease cure has shifted studies toward a series of molecules capable of acting against Aβ and p-tau. Failure of biologics or compounds to cross the blood-brain barrier (BBB) in most cases advocates development of an efficient drug delivery system. Though liposomes and polymeric nanoparticles are widely adopted for drug delivery modules, their use in delivering drugs across the BBB has been overtaken by exosomes, owing to their promising results in reducing disease progression.

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Presenilin-1 Regulates the Expression of p62 to Govern p62-dependent Tau Degradation

Cited by 11 publications

References 76 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

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Perspective Insights into Disease Progression, Diagnostics, and Therapeutic Approaches in Alzheimer's Disease: A Judicious Update

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