A Persistent Stress Response to Impeded Axonal Transport Leads to Accumulation of Amyloid-β in the Endoplasmic Reticulum, and Is a Probable Cause of Sporadic Alzheimer's Disease

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-beta (A beta), triggered by the slowed axonal transport at old age. We hypothesize that A beta 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 A beta 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 Thr(668). This phosphorylation increases the cleavage of APP by the amyloidogenic pathway, which generates A beta 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 A beta 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 A beta in the ER. Our hypothesis could thus explain a pathogenic mechanism in AD. Copyright (C) 2011 S. Karger AG, Basel