Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, Inoue H.
Modeling Alzheimer's disease with iPSCs reveals stress phenotypes associated with intracellular Aβ and differential drug responsiveness.
Cell Stem Cell. 2013 Apr 4;12(4):487-96.
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This extensive, collaborative study brings new evidence supporting the idea that the pathologically relevant amyloid-β peptide (Aβ) is produced and aggregates in compartments in the neuronal soma, including the endosomes, lysosomes, and the endoplasmic reticulum (ER). The generation and oligomerization of Aβ in the ER does not come as a surprise, given that the ER is one of the centers of stress response of the cell. Many types of stress—oxidative, improper protein folding, or the accumulation of proteins in the soma due to impeded transport along the secretory pathway—appear to be sensed by the ER. The ER response, which is geared to relieve the stress-related pathology, is currently widely studied.
The idea that Aβ is generated in the soma, where it accumulates and oligomerizes, is not new (1-3). Also, the idea that stress leads to the generation, accumulation, and oligomerization of Aβ in the endoplasmic reticulum has been previously proposed. For example, we reported that enhanced cleavage of APP in the ER, followed by accumulation and oligomerization of Aβ inside the ER, represents the specific response of the neuron to impeded axonal transport (4)—a situation that becomes an issue in old age (5). It is also likely that part of the oligomeric Aβ produced either in the ER or in the somatic endosomes escapes from these compartments and is transported into neurites, accumulating at their distal tips (2). Although some Aβ could certainly be generated and aggregated at the synapse, emerging evidence, such as that provided by this study, highlights the possibility that pathologically relevant Aβ oligomers are produced in the neuronal soma in neurons affected by Alzheimer's disease. This intraneuronal Aβ could be released in the extracellular space either by cell death or by other mechanisms operating in neurons, such as externalization via exosomes. The field of Alzheimer’s disease is eagerly awaiting new developments in this direction.
Cook DG, Forman MS, Sung JC, Leight S, Kolson DL, Iwatsubo T, Lee VM, Doms RW.
Alzheimer's A beta(1-42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells.
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Muresan V, Muresan Z.
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.
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Muresan V, Muresan Z.
Is abnormal axonal transport a cause, a contributing factor or a consequence of the neuronal pathology in Alzheimer's disease?.
Future Neurol. 2009 Nov 1;4(6):761-773.