RELATIONSHIP OF APP MESSENGER-RNA TRANSCRIPTS AND LEVELS OF NGF AND LOW-AFFINITY NGF RECEPTORS TO BEHAVIORAL MEASURES OF AGE-RELATED COGNITIVE DYSFUNCTION

This study was designed to examine the relationship between cognitive function and endogenous levels of NGF, low-affinity NGF receptor (LNGF R), and amyloid precursor protein (APP) mRNAs. Using 3 month (n = 5), 18 month (n = 40), and 29 month (n = 17) Fischer-344 male rats, cognit ive function was assessed with the Morris water maze, reverse transcri ption and polymerase chain reaction were used to quantify APP mRNAs, a nd NGF and LNGFR levels were determined with an ELISA. Cognitive funct ion declined progressively with age from 3 months to 18 months, and fr om 18 months to 29 months, but only RNA content in the tissue declined significantly from 3 months to 18 months. Between 18 month and 29 mon th rats there were small but statistically significant decreases only for Kunitz protease inhibitor (KPI)-inclusive mRNAs and cortical NGF l evels. There was a small but statistically significant correlation bet ween cognitive function and %KPI (the amount of KPI APP mRNAs relative to the total amount of APP mRNA), with lower %KPI related to more imp aired spatial learning. No other statistically significant correlation or linear relationship could be detected between cognitive function a nd any of the other neurological measures or any combination of these measures (i.e., hippocampal levels of APP 695 mRNA, cortical and hippo campal levels of NGF, and cortical, hippocampal, and basal forebrain r evels of LNGFR). Although there were no strong linear relationships be tween cognitive function and our neurological measures, a past hoc exp loratory cluster analysis suggests that there may be a brief transient increase in tissue revels of %KPI, NGF, and LNGFR during the initial period of cognitive deterioration before substantial neuronal degenera tion has occurred. To test this possibility, levels of these substance s in the tissue, and the number of remaining neurons in which they are being produced will need to be measured independently.