The isolation by our laboratory and others of the gene for the precursor of the Alzheimer's disease amyloid polypeptide, has made it possible to begin dissecting at a molecular level the processes whereby this normal protein may become altered in Alzheimer's disease. The sequence of events which leads to the deposition of the small self-aggregating amyloid peptide in Alzheimer's disease is not known. A key question concerns the causal relationship of amyloid to the pathology of Alzheimer's disease. Projects are proposed to address these questions. In the original application, we proposed to do a detailed analysis of amyloid protein precursor (APP) transcription in defined regions of Alzheimer's disease and normal brains, to test the hypothesis that the development of pathology in Alzheimer's disease is related to changes in the expression of the APP mRNAs.
This specific aim has been completed: we were able to show that the mRNA encoding APRP-563, an APP-related mRNA lacking the amyloid-encoding sequence, is specifically elevated in pathologically affected regions of Alzheimer's disease brain. We have shown, by the construction and characterization of recombinant transfected cell lines expressing particular domains of APP, that the carboxyterminal 105 amino acids of the human amyloid protein precursor is neurotoxic. Studies are proposed to examine the relationship of the neurotoxicity of this fragment (termed AB1) to Alzheimer's disease pathology, by analyzing the pattern of segregation of the microtubule associated protein tau in neurons treated with AB1, and by assaying for differential vulnerability of CA1 hippocampal neurons to AB1 neurotoxicity. Characterization of AB1 neurotoxicity will include definition of the mechanism of glial protection of neurons against AB1 toxicity, determination of the vulnerability of hippocampal neurons from rats of various ages to AB1 neurotoxicity, and assessment of the minimum exposure time of neurons to the AB1 conditioned medium that is necessary to cause their subsequent degeneration. We recently discovered that the neurotoxic AB1 fragment can, under the appropriate conditions, be trophic: experiments to quantify and characterize this trophic effect, and to relate it to the neurotoxicity, are described. Both genetic and pharmacologic methods will be utilized in an attempt to neutralize or block the neurotoxicity of the carboxyterminal 105 amino acids of AB1. The development of alternate methods of synthesis of this AB1 fragment will facilitate the performance of the proposed studies. Studies to follow up on our recent finding that the AB1 fragment binds specifically to the surface of NGF-differentiated PC12 cells but not to undifferentiated PC12 cells, are proposed. Finally, we show that mouse brains transplanted with AB1-transfected PC12 cells demonstrate progressive neurodegeneration in the region of the transplant, and show immunoreactivity with the Alz50 antibody. The possibility of developing these transplanted mice as an animal model for Alzheimer's disease is proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012954-05
Application #
2054807
Study Section
Special Emphasis Panel (ZRG1-NLS-1 (01))
Project Start
1991-09-01
Project End
1999-06-30
Budget Start
1995-07-15
Budget End
1996-06-30
Support Year
5
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Mc Lean Hospital (Belmont, MA)
Department
Type
DUNS #
City
Belmont
State
MA
Country
United States
Zip Code
02478
Laifenfeld, Daphna; Patzek, Lucas J; McPhie, Donna L et al. (2007) Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci 27:7141-53
Neve, Rachael L; McPhie, Donna L (2007) Dysfunction of amyloid precursor protein signaling in neurons leads to DNA synthesis and apoptosis. Biochim Biophys Acta 1772:430-7
Neve, Rachael L; McPhie, Donna L (2006) The cell cycle as a therapeutic target for Alzheimer's disease. Pharmacol Ther 111:99-113
Neve, Rachael L; Neve, Kim A; Nestler, Eric J et al. (2005) Use of herpes virus amplicon vectors to study brain disorders. Biotechniques 39:381-91
Herrup, Karl; Neve, Rachael; Ackerman, Susan L et al. (2004) Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci 24:9232-9
Chen, Yuzhi; Liu, Wenyun; McPhie, Donna L et al. (2003) APP-BP1 mediates APP-induced apoptosis and DNA synthesis and is increased in Alzheimer's disease brain. J Cell Biol 163:27-33
Neve, Rachael L (2003) A new wrestler in the battle between alpha- and beta-secretases for cleavage of APP. Trends Neurosci 26:461-3
McPhie, Donna L; Coopersmith, Robert; Hines-Peralta, Andrew et al. (2003) DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3. J Neurosci 23:6914-27
Carlezon Jr, William A; Neve, Rachael L (2003) Viral-mediated gene transfer to study the behavioral correlates of CREB function in the nucleus accumbens of rats. Methods Mol Med 79:331-50
Chen, Yuzhi; Liu, Wenyun; Naumovski, Louie et al. (2003) ASPP2 inhibits APP-BP1-mediated NEDD8 conjugation to cullin-1 and decreases APP-BP1-induced cell proliferation and neuronal apoptosis. J Neurochem 85:801-9

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