BAG‐1M is up‐regulated in hippocampus of Alzheimer’s disease patients and associates with tau and APP proteins

Elliott, Evan; Laufer, Offir; Ginzburg, Irith

doi:10.1111/j.1471-4159.2009.06047.x

Cited by 34 publications

(22 citation statements)

References 22 publications

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“…It is unclear why increased expression of BAG-1 result in decreased tau degradation, although the authors suggested it could be due to BAG-1 facilitating the refolding of tau and downregulating the pathway that leads to degradation (Elliott, et al, 2007). This same group also reported that an isoform of BAG-1, BAG-1M is increased in the hippocampi of AD patients (Elliott, et al, 2009). In contrast to these studies we found that increasing BAG3 levels in primary neurons alone resulted in a significant decrease in total and phospho-tau levels.…”

Section: Discussionmentioning

confidence: 71%

BAG3 facilitates the clearance of endogenous tau in primary neurons

Lei¹,

Brizzee²,

Johnson³

2015

Neurobiology of Aging

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Tau is a microtubule associated protein that is found primarily in neurons, and in pathological conditions such as Alzheimer disease (AD) it accumulates and contributes to the disease process. Since tau plays a fundamental role in the pathogenesis of AD and other tauopathies, and in AD mouse models reducing tau levels improves outcomes, approaches that facilitate tau clearance are being considered as therapeutic strategies. However, fundamental to the development of such interventions is a clearer understanding of the mechanisms that regulate tau clearance. Here we report a novel mechanism of tau degradation mediated by the co-chaperone BAG3. BAG3 has been shown to be an essential component of a complex that targets substrates to the autophagy pathway for degradation. In rat primary neurons, activation of autophagy by inhibition of proteasome activity or treatment with trehalose resulted in significant decreases in tau and phospho-tau levels. These treatments also induced an upregulation of BAG3. Proteasome inhibition activated JNK, which was responsible for the upregulation of BAG3 and increased tau clearance. Inhibiting JNK or knocking down BAG3 blocked the proteasome inhibition-induced decreases in tau. Further, BAG3 overexpression alone resulted in significant decreases in tau and phospho-tau levels in neurons. These results indicate that BAG3 plays a critical role in regulating the levels of tau in neurons, and interventions that increase BAG3 levels could provide a therapeutic approach in the treatment of AD.

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Section: Discussionmentioning

confidence: 71%

BAG3 facilitates the clearance of endogenous tau in primary neurons

Lei¹,

Brizzee²,

Johnson³

2015

Neurobiology of Aging

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“…Immunoblot analysis was carried out with indicated antibodies, and analysis and quantification were performed by ChemiDoc XRS (Bio-Rad) or by ImageQuant TM TL (General Electrics). Protein from frozen blocks of human hippocampus were obtained from The Netherlands Brain Bank as described previously (28). Proteins were extracted in buffer A (20 mM HEPES, pH 7.4, 0.32 M sucrose, 150 mM KCl, 3 mM MgCl 2 , 10 mM NaF, 20 mM ␤-glycerol phosphate).…”

Section: Methodsmentioning

confidence: 99%

E3 Ligase STUB1/CHIP Regulates NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Accumulation in Aged Brain, a Process Impaired in Certain Alzheimer Disease Patients

Tsvetkov

Adamovich

Elliott

et al. 2011

Journal of Biological Chemistry

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NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that is important in maintaining the cellular redox state and regulating protein degradation. The NQO1 polymorphism C609T has been associated with increased susceptibility to various age-related pathologies. We show here that NQO1 protein level is regulated by the E3 ligase STUB1/CHIP (C terminus of Hsc70-interacting protein). NQO1 binds STUB1 via the Hsc70-interacting domain (tetratricopeptide repeat domain) and undergoes ubiquitination and degradation. We demonstrate here that the product of the C609T polymorphism (P187S) is a stronger STUB1 interactor with increased susceptibility to ubiquitination by the E3 ligase STUB1. Furthermore, age-dependent decrease of STUB1 correlates with increased NQO1 accumulation. Remarkably, examination of hippocampi from Alzheimer disease patients revealed that in half of the cases examined the NQO1 protein level was undetectable due to C609T polymorphism, suggesting that the age-dependent accumulation of NQO1 is impaired in certain Alzheimer disease patients.

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“…For example, Bag-1 interacts with and inhibits the function of the tumor suppressor p73 [8]. Furthermore, the medium isoform, Bag-1M is increased in the hippocampus of Alzheimer's disease patients and binds to Tau protein and amyloid precursor protein (APP), and overexpressed Bag-1M induces increased level of Tau and APP that are related with the pathology and treatment of Alzheimer disease [9,10].…”

Section: Introductionmentioning

confidence: 99%

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

Wang

Baniahmad

et al. 2009

FEBS Letters

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a b s t r a c tThe Bcl-2 associated athanogene 1M (Bag-1M) is known to repress the transactivation of the glucocorticoid receptor (GR). We report here that Bag-1M inhibits the action of GR via recruitment of corepressors, including nuclear receptor corepressor (NcoR) and silencing mediator for retinoic acid and thyroid hormone receptor (SMRT), and histone deacetylase (HDAC)3 to the genomic response element of a glucocorticoid-regulated human metallothionein IIa (hMTIIa) gene. A mutant GR lacking the interaction with BAG-1M fails to recruit the corepressors NcoR and SMRT. RNAi-mediated knock down of corepressors and the use of HDAC inhibitor relieved Bag-1M-induced repression on the transactivation of the GR. In addition, Bag-1M is not involved in the degradation of the receptor. These findings indicate a novel mechanism by which Bag-1M acts as a corepressor and downregulates the activity of the GR. Structured summary:

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BAG‐1M is up‐regulated in hippocampus of Alzheimer’s disease patients and associates with tau and APP proteins

Cited by 34 publications

References 22 publications

BAG3 facilitates the clearance of endogenous tau in primary neurons

BAG3 facilitates the clearance of endogenous tau in primary neurons

E3 Ligase STUB1/CHIP Regulates NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Accumulation in Aged Brain, a Process Impaired in Certain Alzheimer Disease Patients

Bag‐1M inhibits the transactivation of the glucocorticoid receptor via recruitment of corepressors

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