Reduced cerebrospinal fluid levels of α-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits

• Published in: Neuroscience 1999-01, Vol.93 (4), p.1409-1420
• Main Authors: Anderson, J.J., Holtz, G., Baskin, P.P., Wang, R., Mazzarelli, L., Wagner, S.L., Menzaghi, F.
• Format: Article
• Language: English
• Subjects: a-Secretase; ageing; Aging - metabolism; Amyloid beta-Peptides - analysis; Amyloid beta-Peptides - cerebrospinal fluid; Amyloid beta-Protein Precursor - analysis; Amyloid beta-Protein Precursor - cerebrospinal fluid; amyloid precursor protein; Amyloid Precursor Protein Secretases; Animals; Behavioral psychophysiology; Biological and medical sciences; Cerebral Cortex - chemistry; Cerebral Cortex - metabolism; Cognition - physiology; Conditioning (Psychology); Endopeptidases - metabolism; Fundamental and applied biological sciences. Psychology; Hippocampus - chemistry; Hippocampus - metabolism; learning; Male; Maze Learning; memory; Memory Disorders - metabolism; Miscellaneous; Peptide Fragments - analysis; Peptide Fragments - cerebrospinal fluid; Psychology. Psychoanalysis. Psychiatry; Psychology. Psychophysiology; Rats; Rats, Inbred F344; Retention (Psychology); Solubility; Space Perception - physiology; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Visual Acuity; β-amyloid
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/S0306-4522(99)00244-4

The amyloid precursor protein undergoes proteolysis at several sites to yield a number of functionally relevant peptides, including β-amyloid and the soluble amyloid precursor protein derivatives α-soluble amyloid precursor protein and β-soluble amyloid precursor protein. β-Amyloid is the primary constituent of senile plaques associated with Alzheimer's disease, while α-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 α-soluble amyloid precursor protein, total soluble amyloid precursor proteins (α- and β-soluble amyloid precursor protein combined) and β-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 α-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 β-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 α-soluble amyloid precursor protein than did their younger counterparts. There was a positive correlation ( r=0.52–0.57, P