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

Abstract

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<0.001) between performance in spatial memory tasks and cerebrospinal fluid α-soluble amyloid precursor protein in these young and aged rats. These results suggest that there is a positive association between cerebrospinal fluid levels of α-soluble amyloid precursor protein and cognitive performance in rats, and that α-soluble amyloid precursor protein may be involved in the spatial learning and memory changes that accompany ageing.