Alteration in NGF maturation and degradation in subjects with mild cognitive impairment and Alzheimer’s disease

BRUNO, M. A.; COIRINI, H.; MUFSON, E.; CUELLO, A. C.

Hotel 13 de Julio, Ciudad de Mar del Plata, Buenos Aires, Argentina

Congreso; LIII Reunión Anual de la Sociedad Argentina Argentina de Investigación Clínica; 2008

Sociedad Argentina Argentina de Investigación Clínica

The basal forebrain cholinergic neurons (BFCN) are relevant to higher CNS functions such as learning and memory and its deficit are consistently recognized features of Alzheimer's disease (AD).  Importantly, nerve growth factor (NGF) is the most important trophic factor for BFCN and alterations in NGF and it high-affinity receptor (TrkA) have been observed in early and late-stages of AD. In this regard, increased levels of the precursor form of NGF (proNGF) (Peng et al., 2004, Fahnestock et al., 2001) and loss of cortical TrkA (Counts & Mufson., 2005) have been found in subjects with Mild Cognitive Impairment (MCI) and AD. We have found in rodents the involvement of a protease cascade responsible for both the maturation of proNGF to mature NGF and for the degradation of NGF, due to the coordinated release and the action of plasmin and matrix metalloproteinase 9 (MMP-9) (Bruno & Cuello, 2006) Thus, it is plausible that alterations of this cascade in the CNS might cause or contribute to the remarkable vulnerability of BFCN in AD. In AD brains we observed a marked compromise of the protease system leading to alteration in the NGF maturation/degradation pathway, as compared with NCI age-matched controls. To further investigate if this alteration in the NGF maturation/degradation process is altered also in MCI brains, MMP-9 level and activity were analyzed in which proNGF accumulation were previously described. Accordingly, an up-regulation in the Frontal and Parietal cortex proMMP-9 and MMP-9 levels and activity were observed in MCI and AD compared with NCI age-matched controls. Moreover, Frontal cortex MMP-9 levels correlate with MMSE and Global Cognitive Score.  Treating cognition as a categorical variable, both MMP-9 and proMMP-9 were significantly higher in MCI and AD than NCI.  These alterations would explain the failure of NGF support and progressive atrophy of the BFCN associated with learning and memory decline observed at preclinical and early stages of AD.