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 yie ld a number of functionally relevant peptides, including beta-amyloid and t he soluble amyloid precursor protein derivatives alpha-soluble amyloid prec ursor protein and beta-soluble amyloid precursor protein. beta-Amyloid is t he primary constituent of senile plaques associated with Alzheimer's diseas e, while alpha-soluble amyloid precursor protein promotes synaptogenesis an d plays a role in neuroprotective processes. We tested for age-related alte rations 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 precurs or protein combined) and beta-amyloid in cerebrospinal fluid from three-, 1 3- and 23-month-old Fischer-344 rats. Western blot analysis using selective antibodies revealed 50% less total soluble amyloid precursor protein and a lpha-soluble amyloid precursor protein in cisternal cerebrospinal fluid fro m 23-month-old rats compared with three- and 13-month-old animals. Mass spe ctrometric 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, spat ial working and reference memory were assessed in a water maze followed by collection of cerebrospinal fluid. As a group, the aged rats consistently p erformed below the young rats in both working and reference memory tests. T he aged rats also had 49% less cerebrospinal fluid alpha-soluble amyloid pr ecursor protein than did their younger counterparts. There was a positive c orrelation (r = 0.52-0.57, P < 0.001) between performance in spatial memory tasks and cerebrospinal fluid alpha-soluble amyloid precursor protein in t hese young and aged rats. These results suggest that there is a positive association between cerebros pinal 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 agein g. (C) 1999 IBRO. Published by Elsevier Science Ltd.