LEVELS AND ALTERNATIVE SPLICING OF AMYLOID-BETA PROTEIN-PRECURSOR (APP) TRANSCRIPTS IN BRAINS OF APP TRANSGENIC MICE AND HUMANS WITH ALZHEIMERS-DISEASE

Abnormal expression of human amyloid precursor protein (hAPP) gene pro ducts may play a critical role in Alzheimer's disease (AD). Recently, a transgenic model was established in which platelet-derived growth fa ctor (PDGF) promoter-driven neuronal expression of an alternatively sp liced hAPP minigene resulted in prominent AD-type neuropathology (Game s, D., Adams, D., Alessandrini, R., Barbour, R., Berthelette, P., Blac kwell, 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-Zava la, M., Mucke, L., Paganini, L., and Penniman, E. (1995) Nature 373, 5 23-527). Here we compared the levels and alternative splicing of APP t ranscripts in brain tissue of hAPP transgenic and nontransgenic mice a nd of humans with and without AD. PDGF-hAPP mice showed severalfold hi gher levels of total APP mRNA than did nontransgenic mice or humans, w hereas their endogenous mouse APP mRNA levels were decreased. This res ulted 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 se lection with transcripts encoding hAPP770 or hAPP751 being expressed a t substantially higher levels than hAPP695 mRNA. Frontal cortex of hum ans with AD showed a subtle increase in the relative abundance of hAPP 751 mRNA compared with normal controls. These data identify specific i ntron sequences that may contribute to the normal neuron-specific alte rnative splicing of APP pre-mRNA in vivo and support a causal role of hAPP gene products in the development of AD-type brain alterations.