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Sci. Signal., 11 March 2008
Vol. 1, Issue 10, p. ec89
[DOI: 10.1126/stke.110ec89]

EDITORS' CHOICE

Neurobiology Alzheimer’s Signals

L. Bryan Ray

Science, Science Signaling, AAAS, Washington, DC 20005, USA

Alzheimer’s disease is associated with excessive cleavage of the β-amyloid precursor protein (APP) to form the β-amyloid peptide (Aβ), which is thought to contribute to neuronal degeneration. APP can also be cleaved to form the APP intracellular domain (AICD) peptide, which may function analogously to the Notch intracellular domain, a portion of the receptor Notch that is cleaved upon receptor activation and migrates to the nucleus to control transcription. Knowing that a protein known as F3 appears to function as a ligand for Notch, Ma et al. tested whether it or another member of the F3 family of proteins might be a ligand for APP. They go on to show that TAG1 appears to fit the bill. TAG1 functions as a neural cell adhesion molecule with roles in neuronal development. When cultured Chinese hamster ovary cells were transfected with TAG1 from mouse or the homologous human protein, the cells adhered to spots on culture dishes that were coated with APP. Neuronal progenitor cells isolated from mice lacking APP or TAG1 and then differentiated in vitro showed increased expression of markers of differentiated neurons. Analysis of embryos lacking both TAG1 and APP also showed increased neuronal differentiation, indicating that the TAG1 and APP may function to restrain neurogenesis. Mouse embryo fibroblasts transfected with TAG1 produced increased amounts of AICD, consistent with the idea that TAG1 may function as an activating ligand for APP. Transfection of fetal neuronal progenitor cells from TAG1–/– mice with TAG1 decreased the abnormal neurogenesis of the mutant cells but was not effective in cells from animals also lacking APP. Fe65 is a scaffold protein proposed to act with AICD to promote transcription. Experiments with a Fe65-Gal4 fusion protein were consistent with a role of Fe65 downstream of TAG1 and APP. TAG1 also failed to reverse abnormal neurogenesis in neuronal precursor cells from Fe65–/– mice. The authors propose that TAG functions as a ligand for a signaling pathway that includes Fe65 and negatively controls neurogenesis. Commentary from Mattson and van Praag notes that the TAG1 is also present in the adult brain and points out that new results raise the possibility that increased TAG1-APP signaling could contribute in two ways to Alzheimer’s disease--increasing cleavage of APP to form more Aβ (which is formed after a second cleavage of AICD) and decreasing neurogenesis, which may contribute to memory formation in the adult hippocampus.

Q.-H. Ma, T. Futagawa, W.-L. Yang, X.-D. Jiang, L. Zeng, Y. Takeda, R.-X. Xu, D. Bagnard, M. Schachner, A. J. Furley, D. Karagogeos, K. Watanabe, G. S. Dawe, Z.-C. Xiao, A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat. Cell Biol. 10, 283-294 (2008). [PubMed]

M. P. Mattson, H. van Praag, TAGing APP constrains neurogenesis. Nat. Cell Biol. 10, 249-250 (2008). [PubMed]

Citation: L. B. Ray, Alzheimer’s Signals. Sci. Signal. 1, ec89 (2008).



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