Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits.
The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including beta-amyloid and the soluble amyloid precursor protein derivatives alpha-soluble amyloid precursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while a-soluble amyloid precursor protein promotes synaptogenesis and plays a role in neuroprotective processes. We tested for age-related alterations in these amyloid precursor protein proteolytically derived peptides by measuring the levels of alpha-soluble amyloid precursor protein, total soluble amyloid precursor proteins (alpha- and beta-soluble amyloid precursor protein combined) and beta-amyloid in cerebrospinal fluid from three-, 13- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a-soluble amyloid precursor protein in cisternal cerebrospinal fluid from 23-month-old rats compared with three- and 13-month-old animals. Mass spectrometric analysis indicated, however, that beta-amyloid in cerebrospinal fluid was not different between the three age groups. In a second group of young (five to six months of age) and aged (24-25 months of age) rats, spatial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently performed below the young rats in both working and reference memory tests. The aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation (r= 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of alpha-soluble amyloid precursor protein and cognitive performance in rats, and that alpha-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.
Anderson
J J
JJ
Department of Protein Biochemistry, SIBIA Neuosciences Inc., La Jolla, CA 92037, USA. janderson@sibia.com
Holtz
G
G
Baskin
P P
PP
Wang
R
R
Mazzarelli
L
L
Wagner
S L
SL
Menzaghi
F
F
D000375:Aging / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000134:cerebrospinal fluid*; D016564:Amyloid beta-Protein Precursor / Q000032:analysis / Q000134:cerebrospinal fluid*; D000818:Animals; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D003213:Conditioning, Psychological; D010450:Endopeptidases / Q000378:metabolism*; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis / Q000134:cerebrospinal fluid*; D051381:Rats; D011916:Rats, Inbred F344; D012153:Retention, Psychology; D012995:Solubility; D013028:Space Perception / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014792:Visual Acuity
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases