BDNF prevents amyloid-dependent impairment of LTP in the entorhinal cortex by attenuating p38 MAPK phosphorylation

Criscuolo, Chiara; Fabiani, Carlotta; Bonadonna, Camilla; Origlia, Nicola; Domenici, Luciano

doi:10.1016/j.neurobiolaging.2014.11.016

Cited by 61 publications

(47 citation statements)

References 48 publications

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“…Phosphorylation of p38 MAPK has been observed in the postmortem brain in the early stages of AD (Braak stages IV-V) (14, 15). A␤ and glutamate have each been shown to activate p38 MAPK in cultured neurons by increasing reactive oxygen species (16,17), and the A␤-triggered microglial release of inflammatory mediators, especially IL-1␤, is hypothesized to activate neuronal p38 . p38␣ MAPK mediates A␤-initiated microglial inflammatory activation (21, 22), phosphorylates Tau protein in neurons (20,23,24), and mediates A␤-induced synaptic impairment in the cultured hippocampal slice (25).…”

Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

Schnöder

Hao

Qin

et al. 2016

Journal of Biological Chemistry

117

123

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Amyloid ␤ (A␤) damages neurons and triggers microglial inflammatory activation in the Alzheimer disease (AD) brain. BACE1 is the primary enzyme in A␤ generation. Neuroinflammation potentially up-regulates BACE1 expression and increases A␤ production. In Alzheimer amyloid precursor protein-transgenic mice and SH-SY5Y cell models, we specifically knocked out or knocked down gene expression of mapk14, which encodes p38␣ MAPK, a kinase sensitive to inflammatory and oxidative stimuli. Using immunological and biochemical methods, we observed that reduction of p38␣ MAPK expression facilitated the lysosomal degradation of BACE1, decreased BACE1 protein and activity, and subsequently attenuated A␤ generation in the AD mouse brain. Inhibition of p38␣ MAPK also enhanced autophagy. Blocking autophagy by treating cells with 3-methyladenine or overexpressing dominant-negative ATG5 abolished the deficiency of the p38␣ MAPK-induced BACE1 protein reduction in cultured cells. Thus, our study demonstrates that p38␣ MAPK plays a critical role in the regulation of BACE1 degradation and A␤ generation in AD pathogenesis. Alzheimer disease (AD)2 is pathologically characterized by the extracellular deposits of amyloid ␤ peptide (A␤). A␤ injures neurons in the neocortex and limbic system directly (1) and indirectly by triggering microglial release of various neurotoxic inflammatory mediators, including cytokines (tumor necrosis factor-␣ and interleukin-1␤ (IL-1␤)) and reactive oxygen species (2). A␤ is generated after serial digestion of Alzheimer amyloid precursor protein (APP) by the membrane-anchored ␤-site APP-cleaving enzyme (BACE1, ␤-secretase) and ␥-secretase (3). It has been observed that knock-out of BACE1 or administration of the BACE1 inhibitor dramatically decreases A␤ levels in the brain and attenuates behavioral and electrophysiological deficits in APP-transgenic mice (4 -6). Thus, extensive investigations have focused on the direct inhibition of BACE1 to reduce A␤ load in the AD brain; however, these studies have unfortunately not yet led to any efficacious therapy for AD patients due to the various physiological roles of BACE1 (7). Using alternative methods to inhibit BACE1 might be a preferable investigative approach.Inflammatory activation might lead to up-regulation of neuronal BACE1 expression in the AD brain, as NF-B signaling enhances (8), and PPAR␥ activation suppresses (9), the activity of bace1 gene promoter. Accumulating evidence has shown that posttranslational modification of BACE1 is extremely important for the activity, intracellular trafficking, and lysosomal degradation of BACE1. For example, phosphorylation of BACE1 at Thr-252 by p25/Cdk5 increases the secretase activity (10), and phosphorylation at Ser-498 facilitates retrograde transport of BACE1 from endosomes to the trans-Golgi network (11). Ubiquitination at Lys-501 targets BACE1 to late endosomes/lysosomes for degradation (12). Finally, bisecting N-acetylglucosamine modification blocks delivery of BACE1 to lysosomes (13).p38 mitogen-activated protei...

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Section: Alzheimer Disease (Ad)mentioning

confidence: 99%

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

Schnöder

Hao

Qin

et al. 2016

Journal of Biological Chemistry

117

123

View full text Add to dashboard Cite

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“…We raise the hypothesis that ocular hypertension acts as an upstream activator of p38 MAPK; this may contribute to induce retinal dysfunction and degeneration. BDNF has been demonstrated to be a potent growth factor that is beneficial in neurodegenerative diseases with synaptic dysfunction [29], in RGC functions following optic nerve injury and diseases [10,11] and in murine models of glaucoma [18,19]. We should take into account the possibility that BDNF reduces retinal dysfunction in DBA/2J mice with elevated IOP [19] by attenuating p38 MAPK phosphorylation, similarly to what was previously reported for amyloid toxicity [29].…”

Section: Discussionmentioning

confidence: 74%

“…In our murine model, we confirmed that retinal level of activated p38 MAPK increased in concomitance with IOP raise, and reached elevated and growing levels at 10 and 18 months of age. P38 MAPK is activated by a variety of stress stimuli, including osmotic shock, oxidative injury, beta amyloid [29,[35][36]. We raise the hypothesis that ocular hypertension acts as an upstream activator of p38 MAPK; this may contribute to induce retinal dysfunction and degeneration.…”

Section: Discussionmentioning

confidence: 87%

“…BDNF has been demonstrated to be a potent growth factor that is beneficial in neurodegenerative diseases with synaptic dysfunction [29], in RGC functions following optic nerve injury and diseases [10,11] and in murine models of glaucoma [18,19]. We should take into account the possibility that BDNF reduces retinal dysfunction in DBA/2J mice with elevated IOP [19] by attenuating p38 MAPK phosphorylation, similarly to what was previously reported for amyloid toxicity [29]. TrkB activation leads to an enhanced Erk1/2 phosphorylation in RGCs [7] while pharmacological inhibition of ERK1/2 and MEK appears to be responsible for RGC death [37].…”

Section: Discussionmentioning

confidence: 99%

“…It has been demonstrated that ERK1/2 phosphorylation decreases in RGCs following optic nerve transection, whereas its induction is linked to neuroprotection in several experimental models [17,[25][26][27]. On the other hand, p38 MAPK isoforms are phosphorylated in neurons, by stress stimuli, including osmotic shock, excitotoxicity, pro-inflammatory cytokines, oxidative injury and beta amyloid [28,29] and act as upstream activators of myriad pathogenic processes; for example, p38 MAPK phosphorylation induces synaptic dysfunction and activates downstream inflammatory signaling cascades [29,30]. We tested the effect of elevated IOP on BDNF signaling and MAPK activation at an early stage of retinal degeneration characterized by ocular hypertension, and at late stages of retinal degeneration with RGC degeneration and ON atrophy in DBA/2J mice.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Fabiani¹,

Cerri²

2016

J Clin Exp Ophthalmol

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Glaucoma is currently recognized to be a multifactorial, progressive, neurodegenerative disorder. It is characterized by the retinal ganglion cells (RGCs) loss of axons as well as optic nerve atrophy, progressive degeneration of RGCs till cell death. In this work, we used DBA/2J mice as a model of spontaneous glaucoma and we investigated the involvement of BDNF and Mitogen-Activated Protein Kinases (MAPK) pathways in correlation with IOP elevation and progression of neurodegenerative processes in the retina of DBA/2J mice. In particular, we performed western blot analysis to study retinal levels of the BDNF and its receptor, TrkB, and to better understand possible modulation of p38 MAPK and ERK1/2 activation at different stages of retinal degeneration in DBA/2J mice. We showed that BDNF starts to decrease already at an early stage in correspondence to IOP elevation (7 months of age). MAPKs, in particular p38 MAPK and ERK1/2, appeared maximally affected at more advanced stages of neurodegeneration (10-12 and 18 months of age) characterized by RGC degeneration and death, optic nerve atrophy. Thus, BDNF signaling and MAPKs are differentially activated at different stages of retinal degeneration in DBA/2J mice, a murine model of glaucoma.

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Protein Carbonylation in Brains of Subjects with Selected Neurodegenerative Disorders

Reed

Butterfield

2017

Protein Carbonylation

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BDNF prevents amyloid-dependent impairment of LTP in the entorhinal cortex by attenuating p38 MAPK phosphorylation

Cited by 61 publications

References 48 publications

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

Deficiency of Neuronal p38α MAPK Attenuates Amyloid Pathology in Alzheimer Disease Mouse and Cell Models through Facilitating Lysosomal Degradation of BACE1

Changes in BDNF and MAPK Signaling Pathways in Experimental Glaucoma

Protein Carbonylation in Brains of Subjects with Selected Neurodegenerative Disorders

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