Phosphorylation-dependent Regulation of the Interaction of Amyloid Precursor Protein with Fe65 Affects the Production of β-Amyloid

Ando, Kanae; Iijima, Koichi; Elliott, James I.; Kirino, Yutaka; Suzuki, Toshiharu

doi:10.1074/jbc.m104059200

Cited by 242 publications

(279 citation statements)

References 41 publications

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“…Deregulated Cdk5 phosphorylates APP at T668 which increases Aβ formation (Ando et al, 2001). Cdk5 deregulation mediated by p25 overexpression increases the transcription of BACE1 which causes amyloidogenic processing of APP leading to neurotoxic Aβ formation (Wen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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Deregulated Cdk5 causes neurotoxic amyloid beta peptide (Aβ) processing and cell death, two hallmarks of Alzheimer's disease, through the Foxo3 transcriptional factor in hippocampal cells, primary neurons and an Alzheimer's disease mouse model. Using an innovative chemical genetic screen, we identified Foxo3 as a direct substrate of Cdk5 in brain lysates. Cdk5 directly phosphorylates Foxo3, which increased its levels and nuclear translocation. Nuclear Foxo3 initially rescued cells from ensuing oxidative stress by upregulating MnSOD (also known as SOD2). However, following prolonged exposure, Foxo3 upregulated Bim (also known as BCL2L11) and FasL (also known as FASLG) causing cell death. Active Foxo3 also increased Aβ(1-42) levels in a phosphorylationdependent manner. These events were completely inhibited either by expressing phosphorylation-resistant Foxo3 or by depleting Cdk5 or Foxo3, highlighting a key role for Cdk5 in regulating Foxo3. These results were confirmed in an Alzheimer's disease mouse model, which exhibited increased levels and nuclear localization of Foxo3 in hippocampal neurons, which preceded neurodegeneration and Aβ plaque formation, indicating this phenomenon is an early event in Alzheimer's disease pathogenesis. Collectively, these results show that Cdk5-mediated phospho-regulation of Foxo3 can activate several genes that promote neuronal death and aberrant Aβ processing, thereby contributing to the progression of neurodegenerative pathologies.

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Section: Discussionmentioning

confidence: 99%

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Shi

Viccaro

Lee

et al. 2016

Journal of Cell Science

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“…Rabbits were immunized with the purified protein, and the antiserum (anti-JIP-1b) was raised. Anti-APP antibodies, UT18 and G369, were previously described (19,20). The anti-FLAG (M2) and anti-␤-tubulin antibodies were purchased from Sigma, the anti-HA antibody (3F10) from Roche Diagnostics, the anti-APP antibody (6E10) from Signet, the anti-JNK1 antibody from Pharmingen, and the antiphospho-c-Jun and anti-phospho-APP antibodies from Cell Signaling Technology.…”

Section: Methodsmentioning

confidence: 99%

A Scaffold Protein JIP-1b Enhances Amyloid Precursor Protein Phosphorylation by JNK and Its Association with Kinesin Light Chain 1

Inomata

Nakamura

Hayakawa

et al. 2003

Journal of Biological Chemistry

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142

132

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“…In addition to binding APP, Mint proteins can directly bind ADP-ribosylation factors, raising the intriguing possibility that Mints may regulate vesicular trafficking of APP by serving as coat proteins (Hill et al 2003). A conformational change introduced by phosphorylation at Thr-668 (14 amino acids proximal to the YENPTY motif ) interferes with Fe65 binding to APP and facilitates BACE1 and g-secretase cleavage of APP in cultured cells (Ando et al 2001;Lee et al 2003). However, analysis of Thr-668-Ala knock-in mice indicates that the phosphorylation status of Thr-668 does not affect physiological processing of APP into Ab peptides in vivo (Sano et al 2006).…”

Section: Endocytic App Sorting and Ab Productionmentioning

confidence: 99%

Trafficking and Proteolytic Processing of APP

Haass¹,

Kaether²,

Wang³

et al. 2012

Cold Spring Harbor Perspectives in Medicine

911

892

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Accumulations of insoluble deposits of amyloid b-peptide are major pathological hallmarks of Alzheimer disease. Amyloid b-peptide is derived by sequential proteolytic processing from a large type I trans-membrane protein, the b-amyloid precursor protein. The proteolytic enzymes involved in its processing are named secretases. b-and g-secretase liberate by sequential cleavage the neurotoxic amyloid b-peptide, whereas a-secretase prevents its generation by cleaving within the middle of the amyloid domain. In this chapter we describe the cell biological and biochemical characteristics of the three secretase activities involved in the proteolytic processing of the precursor protein. In addition we outline how the precursor protein maturates and traffics through the secretory pathway to reach the subcellular locations where the individual secretases are preferentially active. Furthermore, we illuminate how neuronal activity and mutations which cause familial Alzheimer disease affect amyloid b-peptide generation and therefore disease onset and progression.

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Phosphorylation-dependent Regulation of the Interaction of Amyloid Precursor Protein with Fe65 Affects the Production of β-Amyloid

Cited by 242 publications

References 41 publications

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer's disease models

A Scaffold Protein JIP-1b Enhances Amyloid Precursor Protein Phosphorylation by JNK and Its Association with Kinesin Light Chain 1

Trafficking and Proteolytic Processing of APP

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