A characteristic neuropathological hallmark of Alzheimer's disease (AD) is the neuritic plaque, composed of an extracellular cluster of degenerating nerve terminals with a central core that is composed of deposits of a 4 kDa beta-amyloid peptide (beta-protein). beta-protein is derived from a much larger precursor protein (APP) with a size of between 95-135 kDa. Although the precise etiology and pathogenesis of AD are unknown, strong evidence for the involvement of APP in the cause of AD comes from recent findings in a small number of early onset AD families which carry a mutation on a locus on the APP gene which appears to segregate with the disease. The question of exactly how beta-protein is released from the precursor is of critical importance and remains unanswered. Based on evidence in our published work, we postulated that there were two separate and different processing pathways for APP: the secreted and intracellular pathways. Subsequent work in other laboratories has shown that the secreted pathway results in normal cleavage inside the beta-protein region, resulting in the release of the extracellular fragment of APP. This pathway is unlikely to be the source of intact beta-protein in the brains of Alzheimer's patients since roughly a third of the fragment remains buried in the nerve cell membrane. Our hypothesis, based on data accumulated in this last grant period, is that the source of intact beta-protein in the brains of patients with AD is an intracellular form of APP, since this processing pathway results in progressively smaller, amino terminally cleaved fragments which all span the entire beta-protein region. These may then be potential precursors for intact beta-protein. In this grant application we further extend our hypothesis by proposing possible mechanisms by which an intracellular pathway may arise for an integral membrane protein and propose experiments to test our hypothesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS027580-06
Application #
2266482
Study Section
Neurology A Study Section (NEUA)
Project Start
1989-08-01
Project End
1997-03-31
Budget Start
1995-04-01
Budget End
1996-03-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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

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