The role of the carboxyl-terminal fragments of amyloid precursor protein in Alzheimer's disease.
Two major pathological hallmarks of Alzheimer's disease (AD) are the senile plaques that are primarily composed of amyloid beta-peptide (Abeta) and neurofibrillary tangles consisting of tau aggregates. Abeta is generated proteolytically from a family of Abeta-containing precursor proteins (APP; 695-770 amino acid) by secretase enzymes to different specific carboxyl-terminal fragments (CTFs). Herein we examined APP and its products in autopsied brain sections from 10 AD and 10 non-AD control subjects immunochemically using an antibody that was raised against APP751-770 residue (O443). The O443 antibody was initially characterized by Western blot analysis and immunoprecipitation. In this study, we used this antibody for immunohistochemical analysis to determine the distribution of APP and its CTF species. In 10 brain regions showing different levels of plaques and tangles, antibody O443 stained the perinuclear region of the nucleus, plaques, and neurites. Tangle-bearing neurons also appeared to stain with the antibody, suggesting that these dysfunctional neurons continue to synthesize APP/CTF. Alternatively, the normally short-lived APP/CTF can be stabilized and persist in these neurons. Taken together, these results suggest that, in addition to the widely believed role of Abeta, CTFs may play a key role in the pathogenesis of AD. Studying their localization and biogenesis may reveal the biological activities of CTFs of APP. The present study may pave the way for possible antiamyloidogenic therapy in the treatment of AD.
Lahiri
D K
DK
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA. dlahiri@iupui.edu
Kotwal
G J
GJ
Farlow
M R
MR
Sima
A
A
Kupsky
W
W
Sarkar
F H
FH
Sambamurti
K
K
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D000918:Antibody Specificity; D001344:Autopsy; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D016466:CHO Cells; D006224:Cricetinae; D006801:Humans; D007150:Immunohistochemistry; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments