Aβ Secretion and Plaque Formation Depend on Autophagy

Nilsson, Per; Loganathan, Krishnapriya; Sekiguchi, Masaki; Matsuba, Yukio; Hui, Kelvin; Tsubuki, Satoshi; Tanaka, Motomasa; Iwata, Nobuhisa; Saito, Takashi; Saido, Takaomi C.

doi:10.1016/j.celrep.2013.08.042

Cited by 382 publications

(297 citation statements)

References 26 publications

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“…These accumulated autophagic vacuoles potentially provide membrane structures to produce A␤, as BACE1-cleaved APP and ␥-secretase components are enriched in autophagic vacuoles (57). Moreover, impaired autophagy was reported to promote the intracellular accumulation of A␤ and subsequent neuronal degeneration (58). Thus, inhibition of p38␣ MAPK FIGURE 6. p38␣ MAPK deficiency does not change the phosphorylation of BACE1 in SH-SY5Y cells.…”

Section: Discussionmentioning

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

105

117

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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: Discussionmentioning

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

105

117

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“…Recent reports have shown that autophagy plays a role in unconventional protein secretion in mammalian cells. 11,13,14,22 To examine whether Ab-induced IDE secretion is associated with autophagy, we utilized several autophagic modulators. We found that Ab-induced autophagy is activated in astrocytes ( Fig.…”

Section: Ab Induces Extracellular Secretion Of Functional Ide From Asmentioning

confidence: 99%

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

et al. 2016

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The secretion of proteins that lack a signal sequence to the extracellular milieu is regulated by their transition through the unconventional secretory pathway. IDE (insulin-degrading enzyme) is one of the major proteases of amyloid beta peptide (Ab), a presumed causative molecule in Alzheimer disease (AD) pathogenesis. IDE acts in the extracellular space despite having no signal sequence, but the underlying mechanism of IDE secretion extracellularly is still unknown. In this study, we found that IDE levels were reduced in the cerebrospinal fluid (CSF) of patients with AD and in pathology-bearing AD-model mice. Since astrocytes are the main cell types for IDE secretion, astrocytes were treated with Ab. Ab increased the IDE levels in a time-and concentration-dependent manner. Moreover, IDE secretion was associated with an autophagy-based unconventional secretory pathway, and depended on the activity of RAB8A and GORASP (Golgi reassembly stacking protein). Finally, mice with global haploinsufficiency of an essential autophagy gene, showed decreased IDE levels in the CSF in response to an intracerebroventricular (i.c.v.) injection of Ab. These results indicate that IDE is secreted from astrocytes through an autophagy-based unconventional secretory pathway in AD conditions, and that the regulation of autophagy is a potential therapeutic target in addressing Ab pathology.

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“…Autophagic degradation of tau is regulated by nuclear factor erythroid-2-related factor 2 (Nrf2)-mediated induction of the autophagy receptor NDP52 (Jo et al, 2014) and the Alzheimer's-disease-associated locus phosphatidylinositol binding clathrin assembly protein (PICALM, also known as CALM), which controls the endocytosis of soluble NSF attachment protein receptors (SNAREs) that are involved in the autophagy pathway . Autophagy also regulates amyloid-b production , and defective autophagy leads to the accumulation of intraneuronal amyloid precursor protein (APP) (Nilsson et al, 2013). In microglia, amyloid-b is degraded by autophagy through the autophagy receptor optineurin (Cho et al, 2014) (see poster).…”

Section: Cargo Loading Of Disease-associated Proteinsmentioning

confidence: 99%

Autophagosome dynamics in neurodegeneration at a glance

Wong

Holzbaur

2015

Journal of Cell Science

113

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Autophagy is an essential homeostatic process for degrading cellular cargo. Aging organelles and protein aggregates are degraded by the autophagosome-lysosome pathway, which is particularly crucial in neurons. There is increasing evidence implicating defective autophagy in neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease and Huntington's disease. Recent work using live-cell imaging has identified autophagy as a predominantly polarized process in neuronal axons; autophagosomes preferentially form at the axon tip and undergo retrograde transport back towards the cell body. Autophagosomes engulf cargo including damaged mitochondria (mitophagy) and protein aggregates, and subsequently fuse with lysosomes during axonal transport to effectively degrade their internalized cargo. In this Cell Science at a Glance article and the accompanying poster, we review recent progress on the dynamics of the autophagy pathway in neurons and highlight the defects observed at each step of this pathway during neurodegeneration.

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Aβ Secretion and Plaque Formation Depend on Autophagy

Cited by 382 publications

References 26 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

Insulin-degrading enzyme secretion from astrocytes is mediated by an autophagy-based unconventional secretory pathway in Alzheimer disease

Autophagosome dynamics in neurodegeneration at a glance

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