APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

Zhou, Fangfang; Laar, Theo van; Huang, Huizhe; Zhang, Long

doi:10.1007/s13238-011-1047-9

Cited by 59 publications

(33 citation statements)

References 24 publications

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“…However, it remains controversial whether full-length APP is processed in autophagy. Recently, it was shown that APP can be found accumulated in autophagic compartments and that APP and its paralogue APLP1 are substrates for autophagy (16,43). It also was found that BEC1 reduces cellular APP levels, and its deficiency alters APP metabolism (16).…”

Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

Parr

Carzaniga

Gentleman

et al. 2012

Molecular and Cellular Biology

151

107

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dAlzheimer's disease (AD) has been associated with altered activity of glycogen synthase kinase 3 (GSK3) isozymes, which are proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. However, the molecular basis by which GSK3 affects the formation of A␤ remains unknown. Our aim was to identify the underlying mechanisms of GSK3-dependent effects on the processing of amyloid precursor protein (APP). For this purpose, N2a cells stably expressing APP carrying the Swedish mutation were treated with specific GSK3 inhibitors or transfected with GSK3␣/␤ short interfering RNA. We show that inhibition of GSK3 leads to decreased expression of APP by enhancing its degradation via an increase in the number of lysosomes. This induction of the lysosomal/autophagy pathway was associated with nuclear translocation of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Our data indicate that GSK3 inhibition reduces A␤ through an increase of the degradation of APP and its carboxy-terminal fragment (CTF) by activation of the lysosomal/autophagy pathway. These results suggest that an increased propensity toward autophagic/lysosomal alterations in AD patients could have consequences for neuronal function. The Ser/Thr kinase glycogen synthase kinase 3 (GSK3) has been shown to be a key regulator in the molecular pathogenesis of Alzheimer's disease (AD). The two isozymes of GSK3, ␣ and ␤, display nearly identical sequences in their kinase domains, but not much is known about their isoform-specific function (17).GSK3 activity might be increased in AD through changes in its phosphorylation state as well as expression levels, although direct evidence for this is still limited at present (4, 22). GSK3 has been proposed to contribute to both neurofibrillary tangles and amyloid plaque formation. This is based on evidence that GSK3 phosphorylates protein tau and also amyloid precursor protein (APP), thereby promoting A␤ production (3). GSK3␤ transgenic mice have impaired long-term potentiation (LTP) in CA1, while the induction of LTP appears to decrease kinase activity as indicated by phosphorylation of Ser9 (13,14). In addition, tyrosine phosphorylation of GSK3 is increased in AD transgenic mice early in life by soluble amyloid species (38). Interestingly, exposure of hippocampal neurons to A␤ has been shown to increase GSK3␤ activity (36). As active GSK3␤ triggers not only phosphorylation of tau but also other events that could contribute to cell death, a major part of AD pathology could result from increased GSK3 activity.On the other hand, treatment with LiCl, a well-known and widely used but nonspecific GSK3 inhibitor in cultured neuronal cells and Tg2576 mice, resulted in different outcomes, from reduced A␤40 and A␤42 loads (23,34,35) to increased A␤ generation (6,8). A recent study treating the double transgenic APP/Tau mouse model with a novel specific GSK3 inhibitor resulted in lower levels of tau phosphorylation, decreased A␤ deposition and plaque-associated astrocytic proliferation,...

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Section: Discussionmentioning

confidence: 99%

Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

Parr

Carzaniga

Gentleman

et al. 2012

Molecular and Cellular Biology

151

107

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“…As previously described Zhou et al, 2011aZhou et al, , 2011b, total RNAs were prepared using NucleoSpin® RNA II kit. Expression level of target genes was normalized with GAPDH.…”

Section: Real-time Reverse Transcription (Rt)-pcrmentioning

confidence: 99%

Suppression of GSK3β by ERK mediates lipopolysaccharide induced cell migration in macrophage through β-catenin signaling

et al. 2012

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We investigate the role of β-catenin signaling in the response of macrophage to lipopolysaccharide (LPS) using RAW264.7 cells. LPS rapidly stimulated cytosolic β-catenin accumulation. β-catenin-mediated transcription was showed to be required for LPS induced gene expression and cell migration. Mechanically, ERK activation-primed GSK3β inactivation by Akt was demonstrated to mediate the LPS induced β-catenin accumulation. Overall, our findings suggest that suppression of GSK3β by ERK stimulates β-catenin signaling therefore contributes to LPS induced cell migration in macrophage activation.

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“…First of all, autophagy is believed to be another major Aβ clearance pathway besides those well-known Aβ degradation enzymes [56]. Autophagy facilitates the degradation and clearance of APP [57] as well as all APP cleavage products including Aβ [47,58], and APP-CTFs (amyloid precursor protein cleaved C-terminal fragment) [59]. In microglia, Aβ has also been found to be degraded by autophagy through the autophagy receptor optineurin [60].…”

Section: Autophagy Dysfunction and Ad-related Pathologymentioning

confidence: 99%

The role of autophagy in Alzheimer's disease

Li¹,

Sun²

2017

J Syst Integr Neurosci

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Autophagy is a key pathway to clear cellular abnormal protein aggregates, and is essential for protein homeostasis and neuronal health. Several studies have shown autophagy deficits may occur in early stage of Alzheimer's disease (AD). Regarding to Alzheimer's disease, autophagy itself plays an important role in generation and metabolism of β-amyloid (Aβ), assembling of tau and thus its dysfunction may lead to the progress or aggravate of AD. By considering all published evidences, autophagy may be considered as a new target for developing AD targeted drugs. So far, a number of mammalian target of rapamycin (mTOR)-dependent and independent autophagy modulators have been identified to have positive effects in AD treatment. In this review, we summarized the latest progress supporting the role for autophagy deficits in AD, and the potential therapeutic effects of autophagy modulators in AD.

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APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

Cited by 59 publications

References 24 publications

Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

Glycogen Synthase Kinase 3 Inhibition Promotes Lysosomal Biogenesis and Autophagic Degradation of the Amyloid-β Precursor Protein

Suppression of GSK3β by ERK mediates lipopolysaccharide induced cell migration in macrophage through β-catenin signaling

The role of autophagy in Alzheimer's disease

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