Regulatory region of human amyloid precursor protein (APP) gene promotes neuron-specific gene expression in the CNS of transgenic mice.
The accumulation of beta-amyloid protein in specific brain regions is a central pathological feature of Alzheimer's disease (AD). The 4 kd beta-amyloid protein derives from a larger amyloid precursor protein (APP) by as yet unknown mechanisms. In the absence of a laboratory animal model of AD, transgenic mice expressing various APP gene products may provide new insights into the relationship between APP and beta-amyloid formation and the pathogenesis of AD. beta-amyloid accumulation in AD brain may result from interactions between APP and other molecules. Such interactions are likely to be developmentally regulated and tissue-specific. A transgenic mouse model of AD, therefore, would aim for APP transgene expression that mimics the endogenous APP gene. As an initial step in developing an animal model, we have identified a 4.5 kb DNA fragment from the 5' end of the human APP gene, which mediates neuron-specific gene expression in the CNS of transgenic mice, using E. coli lacZ as a reporter gene. Detectable levels of transgene expression are found in most neurons but not in glial and vascular endothelial cells. The expression pattern of this reporter gene closely resembles the distribution of endogenous APP mRNA in both the human and mouse CNS.
Wirak
D O
DO
Molecular Therapeutics Inc., Miles Research Center, West Haven, CT 06516.
Bayney
R
R
Kundel
C A
CA
Lee
A
A
Scangos
G A
GA
Trapp
B D
BD
Unterbeck
A J
AJ
D000544:Alzheimer Disease / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics*; D016564:Amyloid beta-Protein Precursor; D000818:Animals; D001921:Brain / Q000378:metabolism*; D003001:Cloning, Molecular; D015870:Gene Expression; D005809:Genes, Regulator; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009693:Nucleic Acid Hybridization; D009928:Organ Specificity; D011498:Protein Precursors / Q000032:analysis / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000032:analysis; D015183:Restriction Mapping; D001616:beta-Galactosidase / Q000032:analysis / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D011498:Protein Precursors; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D001616:beta-Galactosidase