NDLI: Levels and Alternative Splicing of Amyloid β Protein Precursor (APP) Transcripts in Brains of APP Transgenic Mice and Humans with Alzheimer's Disease

Content Provider	Journal of Biological Chemistry (JBC)
Author	Rockenstein, Edward M. McConlogue, Lisa Tan, Hua Power, Mike Masliah, Eliezer Mucke, Lennart
Abstract	Abnormal expression of human amyloid precursor protein (hAPP) gene products may play a critical role in Alzheimer's disease (AD). Recently, a transgenic model was established in which platelet-derived growth factor (PDGF) promoter-driven neuronal expression of an alternatively spliced hAPP minigene resulted in prominent AD-type neuropathology (Games, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., Guido, T., Hagopian, S., Johnson-Wood, K., Khan, K., Lee, M., Leibowitz, P., Lieberburg, I., Little, S., Masliah, E., McConlogue, L., Montoya-Zavala, M., Mucke, L., Paganini, L., and Penniman, E.(1995) Nature 373, 523-527). Here we [Medline] compared the levels and alternative splicing of APP transcripts in brain tissue of hAPP transgenic and nontransgenic mice and of humans with and without AD. PDGF-hAPP mice showed severalfold higher levels of total APP mRNA than did nontransgenic mice or humans, whereas their endogenous mouse APP mRNA levels were decreased. This resulted in a high ratio of mRNAs encoding mutated hAPP versus wild-type mouse APP. Modifications of hAPP introns 6, 7, and 8 in the PDGF-hAPP construct resulted in a prominent change in alternative splice site selection with transcripts encoding hAPP770 or hAPP751 being expressed at substantially higher levels than hAPP695 mRNA. Frontal cortex of humans with AD showed a subtle increase in the relative abundance of hAPP751 mRNA compared with normal controls. These data identify specific intron sequences that may contribute to the normal neuron-specific alternative splicing of APP pre-mRNA in vivo and support a causal role of hAPP gene products in the development of AD-type brain alterations.
Related Links	http://www.jbc.org/content/270/47/28257.abstract
Ending Page	28267
Starting Page	28257
Page Count	11
File Format	HTM / HTML PDF
ISSN	00219258
Journal	Journal of Biological Chemistry (JBC)
Issue Number	47
Volume Number	270
DOI	10.1074/jbc.270.47.28257
e-ISSN	1083351X
Language	English
Publisher	American Society for Biochemistry and Molecular Biology
Publisher Date	1995-11-24
Access Restriction	Open
Subject Keyword	Nucleic Acids, Protein Synthesis, and Molecular Genetics
Content Type	Text
Resource Type	Article
Subject	Cell Biology Biochemistry Molecular Biology

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