Mutations in the genes for the beta-amyloid precursor protein (beta- APP), a type 1 single-membrane spanning integral protein, and the more recently identified closely homologous seven-membrane spanning integral proteins S182 and STM2, together account for all early-onset familial Alzheimer's disease. The normal functions of the three proteins are not known nor do we know how their functions are implicated in the disease. They recently proposed (Science, 271, 159-160, 1996) based on precedents in other system of an integral proteins, that one or more forms of beta-APP and S182 (or STM2) may normally be components of an intercellular signaling system. Beta-APP and S182 or STM2 on the surfaces of neighboring cells would bind to one another specifically through their extra-cellular domains protruding from the dell membranes, beta-amyloid (Abeta) being a proteolytic by-product of this interaction. To test this proposal full-length cDNAs for S182 and STM2 were cloned by PCR and subcloned into pcDNA3. Beta- APP695 cDNA was also subcloned into pcDNA3 and the constructs were used to transiently transfect cultured cells. Polyclonal antibodies raised to peptide sequences of STM2 and S182 demonstrated the presence of the two proteins at the surface of transfected cells. In order to determine if STM2 or S182 on one cell interacts with beta- APP on another, transfected cells expressing STM2 or S182 were mixed with cells expressing beta-APP. Heterotypic cell aggregates were formed, as shown by double labeling with antibodies to beta-APP and STM2 (or S182). Furthermore, this aggregation could be inhibited by excess soluble beta-APP, indicating specificity of the interaction. Our work provides evidence for the direct physical interaction of beta- APP with STM2 and S182, which may be crucial to the generation of Abeta and the genesis of Alzheimer's disease. To further test our hypothesis, in this application we propose, among other things, to investigate if transcellular binding between beta-APP and S182/STM2 results in vesicular internalization of the two proteins, the release of more or longer form of Abeta and normal signaling.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Neurology A Study Section (NEUA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Dewji, Nazneen N; Mukhopadhyay, Debashis; Singer, S Jonathan (2006) An early specific cell-cell interaction occurs in the production of beta-amyloid in cell cultures. Proc Natl Acad Sci U S A 103:1540-5
Singer, S Jonathan; Dewji, Nazneen N (2006) Evidence that Perutz's double-beta-stranded subunit structure for beta-amyloids also applies to their channel-forming structures in membranes. Proc Natl Acad Sci U S A 103:1546-50
Dewji, Nazneen N (2006) Presenilin structure in mechanisms leading to Alzheimer's disease. J Alzheimers Dis 10:277-90
Dewji, N N (2005) The structure and functions of the presenilins. Cell Mol Life Sci 62:1109-19
Dewji, Nazneen N; Valdez, Dante; Singer, S J (2004) The presenilins turned inside out: implications for their structures and functions. Proc Natl Acad Sci U S A 101:1057-62
Dewji, N N; Singer, S J (1996) Specific transcellular binding between membrane proteins crucial to Alzheimer disease. Proc Natl Acad Sci U S A 93:12575-80
Dewji, N N; Do, C (1996) Heat shock factor-1 mediates the transcriptional activation of Alzheimer's beta-amyloid precursor protein gene in response to stress. Brain Res Mol Brain Res 35:325-8
Dewji, N N; Do, C; Bayney, R M (1995) Transcriptional activation of Alzheimer's beta-amyloid precursor protein gene by stress. Brain Res Mol Brain Res 33:245-53
Trejo, J; Massamiri, T; Deng, T et al. (1994) A direct role for protein kinase C and the transcription factor Jun/AP-1 in the regulation of the Alzheimer's beta-amyloid precursor protein gene. J Biol Chem 269:21682-90
Adler, M J; Coronel, C; Shelton, E et al. (1991) Increased gene expression of Alzheimer disease beta-amyloid precursor protein in senescent cultured fibroblasts. Proc Natl Acad Sci U S A 88:16-20

Showing the most recent 10 out of 11 publications