Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

Mohamed, Nguyen‐Vi; Plouffe, Vanessa; Rémillard-Labrosse, Gaudeline; Planel, Emmanuel; Leclerc, Nicole

doi:10.1038/srep05715

Cited by 79 publications

(82 citation statements)

References 67 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Importantly, trehalose was shown to enhance ␣-synuclein secretion in PC12 catecholaminergic nerve cells (47). In addition, increased secretion of tau was also observed upon starvation and lysosomal inhibition in primary neurons, likely caused by release of autophagosomal contents into extracellular fluids (48). In our experiments, cellular levels of endogenously expressed tau and ␣-synuclein were not affected by trehalose (data not shown).…”

Section: Discussionmentioning

confidence: 48%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

The disaccharide trehalose is commonly considered to stimulate autophagy. Cell treatment with trehalose could decrease cytosolic aggregates of potentially pathogenic proteins, including mutant huntingtin, ␣-synuclein, and phosphorylated tau that are associated with neurodegenerative diseases. Here, we demonstrate that trehalose also alters the metabolism of the Alzheimer disease-related amyloid precursor protein (APP). Cell treatment with trehalose decreased the degradation of full-length APP and its C-terminal fragments. Trehalose also reduced the secretion of the amyloid-␤ peptide. Biochemical and cell biological experiments revealed that trehalose alters the subcellular distribution and decreases the degradation of APP C-terminal fragments in endolysosomal compartments. Trehalose also led to strong accumulation of the autophagic marker proteins LC3-II and p62, and decreased the proteolytic activation of the lysosomal hydrolase cathepsin D. The combined data indicate that trehalose decreases the lysosomal metabolism of APP by altering its endocytic vesicular transport.Alzheimer disease is characterized by the accumulation of extracellular amyloid plaques that contain aggregates of the amyloid ␤-peptide (A␤).5 A␤ is derived from the amyloid precursor protein by sequential proteolytic processing by ␤-and ␥-secretases (1, 2). The initial cleavage of amyloid precursor protein (APP) by ␤-secretase results in the secretion of the soluble ectodomain and the generation of a membrane-tethered C-terminal fragment (APP-CTF␤). Subsequently, APP-CTF␤ can be cleaved by ␥-secretase to liberate A␤ from cellular membranes (2). In an alternative pathway, APP can also be cleaved by ␣-secretase within the A␤ domain, thereby generating CTF␣. The subsequent cleavage of APP-CTF␣ by ␥-secretase results in secretion of a small peptide called p3 (2). It is important to note that APP is also metabolized by additional pathways, including proteasomal and lysosomal degradation (3-5).The metabolism of APP is also regulated by macroautophagy (herein referred to as autophagy), a lysosome-dependent degradative pathway for long lived proteins, organelles, and nutrient recycling (6, 7). Autophagy starts with the formation of double-membrane vesicles, the so-called autophagosomes, which further fuse with lysosomes to become autolysosomes for degradation of autophagosome contents by lysosomal hydrolases (8). Autophagy is an essential prosurvival pathway induced by a variety of stress factors, including nutrient deprivation, growth factor withdrawal, oxidative stress, infection, and hypoxia (9). These factors contribute to the etiology of multiple diseases such as cancer, stroke, heart disease, and infection (10). Eukaryotic cells have a basal autophagic activity under normal physiological conditions. Cells deficient in autophagy show diffuse abnormal protein accumulation and mitochondrial disorganization (11,12), suggesting that autophagy is important to maintain cellular homeostasis by eliminating protein aggregates and damaged organelles. Basal ...

show abstract

Section: Discussionmentioning

confidence: 48%

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tiên¹,

Karaca²,

Tamboli³

et al. 2016

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Although S199 phosphorylation is also found in tauopathies and promotes tau accumulation (Hanger et al, 2009), we report a relative loss of S199 phosphorylation in experimental glaucoma. Accumulating evidence indicates that some stress signals, including oxidative stress, excitotoxicity, and starvation, do not induce hyperphosphorylation but rather hypophosphorylation of tau (Davis et al, 1997;Kuszczyk et al, 2009;Mohamed et al, 2014). Furthermore, tau dephosphorylation has been reported following ischemia, hypoxia, and glucose deprivation in in vivo models and in human brain tissue (Shackelford and Nelson, 1996;Burkhart et al, 1998;Shackelford and Yeh, 1998;Mailliot et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

et al. 2016

View full text Add to dashboard Cite

Glaucoma, the leading cause of irreversible blindness worldwide, is characterized by the selective death of retinal ganglion cells (RGCs). Ocular hypertension is the most significant known risk factor for developing the disease, but the mechanism by which elevated pressure damages RGCs is currently unknown. The axonal-enriched microtubule-associated protein tau is a key mediator of neurotoxicity in Alzheimer's disease and other tauopathies. Using a well characterized in vivo rat glaucoma model, we show an age-related increase in endogenous retinal tau that was markedly exacerbated by ocular hypertension. Early alterations in tau phosphorylation, characterized by epitope-dependent hyperphosphorylation and hypophosphorylation, correlated with the appearance of tau oligomers in glaucomatous retinas. Our data demonstrate the mislocalization of tau in the somatodendritic compartment of RGCs subjected to high intraocular pressure. In contrast, tau was depleted from RGC axons in the optic nerve of glaucomatous eyes. Importantly, intraocular administration of short interfering RNA against tau effectively reduced retinal tau accumulation and promoted robust survival of RGC somas and axons, supporting a critical role for tau alterations in ocular hypertension-induced neuronal damage. Our study reveals that glaucoma displays signature pathological features of tauopathies, including tau accumulation, altered phosphorylation, and missorting; and identifies tau as a novel target to counter RGC neurodegeneration in glaucoma and prevalent optic neuropathies.

show abstract

“…Primary cortical neurons were prepared from E16 mouse embryos (C57BL/6J mice) as previously described [27]. Cells were grown in Neurobasal medium supplemented with 2% B27 and GlutaMAX.…”

Section: Primary Cortical Neuron Culturesmentioning

confidence: 99%

Edaravone Attenuates the Proinflammatory Response in Amyloid-β-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

Wang

Zhang

Huang

et al. 2017

Cell Physiol Biochem

View full text Add to dashboard Cite

Background/Aims: Microglial activation is an important pathological feature in the brains of patients with Alzheimer's disease (AD), and amyloid-β (Aβ) peptides play a crucial role in microglial activation. In addition, edaravone (EDA) was recently shown to suppress oxidative stress and proinflammatory cytokine production in APPswePS1dE9 (APP/PS1) mice. However, the mechanism by which EDA inhibits the Aβ-induced proinflammatory response in microglia is poorly understood. Methods: The mitochondrial membrane potential (Dψm) was evaluated using JC-1 staining. Intracellular reactive oxygen species (ROS) and mitochondrial ROS levels were detected using CM-H2DCFDA and MitoSOX TM Red, respectively. The levels of CD11b, NLRP3, pro-caspase-1 and manganese superoxide dismutase (SOD-2) were observed by western blotting, and the levels of interleukin-1beta (IL-1β) in culture supernatants were quantified using an ELISA kit. Results: Aβ induced microglia activation and mitochondrial dysfunction. In addition, mitochondrial dysfunction was associated with ROS accumulation and activation of the NLRP3 inflammasome. Importantly, Aβ induced activation of the NLRP3 inflammasome, leading to caspase-1 activation and IL-1β release in microglia. Moreover, EDA obviously attenuated the depolarization of Δψm, reduced mitochondria-derived ROS production and increased SOD-2 activity, resulting in the suppression of NLRP3 inflammasomemediated IL-1β secretion in Aβ-treated microglia. Conclusion: EDA is a mitochondria-targeted antioxidant and exhibits anti-inflammatory effects on Aβ-treated microglia.

show abstract

Starvation and inhibition of lysosomal function increased tau secretion by primary cortical neurons

Cited by 79 publications

References 67 publications

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Trehalose Alters Subcellular Trafficking and the Metabolism of the Alzheimer-associated Amyloid Precursor Protein

Tau Accumulation, Altered Phosphorylation, and Missorting Promote Neurodegeneration in Glaucoma

Edaravone Attenuates the Proinflammatory Response in Amyloid-β-Treated Microglia by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion

Contact Info

Product

Resources

About