Neuronal expression of beta-amyloid precursor protein Alzheimer mutations causes intracellular accumulation of a C-terminal fragment containing both the amyloid beta and cytoplasmic domains.
Five different Alzheimer mutations of the beta-amyloid precursor protein (APP) were expressed in neurons via recombinant herpes simplex virus (HSV) vectors, and the levels of APP metabolites were quantified. The predominant intracellular accumulation product was a C-terminal fragment of APP that co-migrated with the protein product of an HSV recombinant expressing the C-terminal 100 amino acids (C100) of APP, which is known to cause neurodegeneration. Fractionation studies revealed that the C-terminal fragment generated by expression of the Alzheimer mutations, like C100, partitioned into membrane fractions and was particularly enriched in synaptosomes. The processing abnormality caused by expression of the Alzheimer mutations occurs predominantly in neurons. Expression of these mutations or of C100 alone in neurons caused increased secretion of Abeta relative to that of neurons infected with wild type APP recombinant vectors. These data show that expression of APP mutations that cause familial Alzheimer's disease increases the intracellular accumulation of potentially amyloidogenic and neurotoxic C-terminal fragments of APP in neurons.
McPhie
D L
DL
Department of Genetics, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02178, USA.
Lee
R K
RK
Eckman
C B
CB
Olstein
D H
DH
Durham
S P
SP
Yager
D
D
Younkin
S G
SG
Wurtman
R J
RJ
Neve
R L
RL
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000737:chemistry; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry; D017354:Point Mutation; D051381:Rats; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D018139:Simplexvirus; D014162:Transfection
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; D011994:Recombinant Proteins