Editors' ChoiceNeuroscience

From Amyloid to ATF4, Axons Mediate Neuron Loss

Sci. Signal.  16 Sep 2014:
Vol. 7, Issue 343, pp. ec250
DOI: 10.1126/scisignal.2005898

Alzheimer’s disease is a neurodegenerative disease associated with β-amyloid (Aβ) plaques. Baleriola et al. investigated the mechanism by which pathogenic Aβ-induced changes in axonal projections cause cell death in the neurons using rat embryonic hippocampal neurons cultured in tripartite chambers, which enable the axons and cell bodies (soma) to be exposed to different media. Addition of oligomeric Aβ1-42 to the axonal chamber induced apoptosis in neurons that depended on increased general protein synthesis specifically in the axons. Aβ1-42 stimulated the expression of a specific set of mRNAs in the axons but not in the soma, among which was the transcript for activating transcription factor 4 (ATF4). ATF4 suppresses the transcription of memory-related genes and activates the expression of apoptosis-related genes as part of the unfolded protein response (UPR), a pathway induced by cellular stress. The translation of ATF4 is mediated by the translation initiation factor eIF2α. Exposure of axons to Aβ1-42 resulted in a temporal response: First, the abundance of eIF2α increased in the axons, then ATF4 increased in the axons, and finally ATF4 abundance increased in the soma. Inhibiting retrograde transport blocked the responses to Aβ1-42 in the soma but not the increase of ATF4 in the axons. Furthermore, blocking retrograde transport also prevented Aβ1-42 from stimulating ATF4-mediated transcriptional induction of CHOP (a UPR mediator) in the soma and prevented neuron death when axons were treated with Aβ1-42. Knocking down ATF4 also prevented Aβ1-42-induced neuronal death. Intrahippocampal injection of Aβ1-42 in mice induced cell death in basal forebrain cholinergic neurons (BFCN), which extend their axons to the hippocampus. BFCN axons in the Aβ1-42-injected hippocampus had increased abundance of Atf4 mRNA; ATF4 protein was increased in both BFCN axons and soma. Coinjection of ATF4 siRNA decreased Aβ1-42-induced BFCN death but exacerbated cell death in the hippocampus. In postmortem brain tissue from patients that had Alzheimer’s disease, ATF4-positive axons were observed in the vicinity of Aβ plaques. Thus, blocking the transport of ATF4 from axons to the soma may prevent some of the neuronal loss associated with Alzheimer’s disease.

J. Baleriola, C. A. Walker, Y. Y. Jean, J. F. Crary, C. M. Troy, P. L. Nagy, U. Hengst, Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell 158, 1159–1172 (2014). [PubMed]