Background and Objective: Could a normal – but persistent – stress response to impeded axonal transport lead to late-onset Alzheimer’s disease (AD)? Our results offer an affirmative answer, suggesting a mechanism for the abnormal production of amyloid-β (Aβ), triggered by the slowed axonal transport at old age. We hypothesize that Aβ precursor protein (APP) is a sensor at the endoplasmic reticulum (ER) that detects, and signals to the nucleus, abnormalities in axonal transport. When persistently activated, due to chronically slowed-down transport, this signaling pathway leads to accumulation of Aβ within the ER. Methods and Results: We tested this hypothesis with the neuronal cell line CAD. We show that, normally, a fraction of APP is transported into neurites by recruiting kinesin-1 via the adaptor protein, Fe65. Under conditions that block kinesin-1-dependent transport, APP, Fe65 and kinesin-1 accumulate in the soma, and form a complex at the ER. This complex recruits active c-Jun N-terminal kinase (JNK), which phosphorylates APP at Thr668. This phosphorylation increases the cleavage of APP by the amyloidogenic pathway, which generates Aβ within the ER lumen, and releases Fe65 into the cytoplasm. Part of the released Fe65 translocates into the nucleus, likely to initiate a gene transcription response to arrested transport. Prolonged arrest of kinesin-1-dependent transport could thus lead to accumulation and oligomerization of Aβ in the ER. Conclusion: These results support a model where the APP:Fe65 complex is a sensor at the ER for detecting the increased level of kinesin-1 caused by halted transport, which signals to the nucleus, while concomitantly generating an oligomerization-prone pool of Aβ in the ER. Our hypothesis could thus explain a pathogenic mechanism in AD.
© 2011 S. Karger AG, Basel
- Alzheimer’s disease
- Amyloid-β precursor protein
- Amyloid-β peptide
- Axonal transport
- Endoplasmic reticulum stress
- Protein phosphorylation
- Mechanism of neurodegenerative diseases
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Department of Pharmacology and Physiology
University of Medicine and Dentistry of New Jersey, New Jersey Medical School
185 South Orange Avenue, MSB, I-665, Newark, NJ 07101-1709 (USA)
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Received: June 28, 2011
Accepted after revision: September 3, 2011
Published online: December 7, 2011
Number of Print Pages : 4
Number of Figures : 4, Number of Tables : 0, Number of References : 20
Vol. 10, No. 1-4, Year 2012 (Cover Date: April 2012)
Journal Editor: Nitsch R.M. (Zürich), Hock C. (Zürich)
ISSN: 1660-2854 (Print), eISSN: 1660-2862 (Online)
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