Progression of age-associated cognitive impairment correlates with quantitative and qualitative loss of TrkA receptor protein in nucleus basalis and cortex H. Uri Saragovi Department of Pharmacology and Therapeutics, Oncology/Cancer Center, McGill University, Lady Davis Institute-Jewish General Hospital, Montreal, Quebec, Canada Abstract A direct correlation between disease progression and reduced expression of TrkA receptor in cholinergic neurons has been documented in neurocognitive pathologies including Alzhei- mer’s disease. We investigated whether reduced expression of TrkA protein might also correlate with the level of cognitive impairment in age-associated cognitive impairment. Quanti- tative and qualitative measurements of TrkA protein levels in the cortex and nucleus basalis of aged rats that had been well- characterized behaviorally as ‘unimpaired’, ‘mildly impaired’ or ‘fully impaired’ demonstrated significant changes in TrkA expression. In the mildly impaired cognitive state phenotypic silencing of TrkA was detected in neurons expressing TrkA at high density but before cholinergic atrophy or loss of TrkA + neurons was detected. In the fully impaired cognitive state a significant loss in TrkA + cholinergic neurons together with a more significant phenotypic silencing of TrkA expression then took place. These data suggest that TrkA + cholinergic cells are associated with cognition, TrkA could be a biomarker of the cognitive state and phenotypic loss of TrkA precedes neuronal loss and probably sensitizes cells to death. We speculate that neurotrophic deficits may be a shared mech- anism for cognitive decline in aging and Alzheimer’s disease. Keywords: Alzheimer’s disease, cholinergic, cognition, nerve growth factor, TrkA. J. Neurochem. (2005) 95, 1472–1480. Cholinergic projection neurons of the basal forebrain nucleus basalis (NB) provide the major source of cholinergic innervation to the cerebral cortex (Mesulam et al. 1983) and play a key role in memory and attention (Coyle et al. 1983; Bartus 2000). During normal aging, these neurons can undergo slow atrophy and degeneration, while in Alzhei- mer’s disease (AD) and Down’s syndrome neuronal degen- eration can occur faster and be more extensive. These findings suggest that reduced cortical–NB choliner- gic transmission may contribute to symptoms involving memory loss (Whitehouse et al. 1981; DeKosky et al. 1992; Bartus 2000). However, the pathogenic mechanisms under- lying NB degeneration and memory loss in aging, AD and Down’s syndrome are still not fully understood. In some way AD and Down’s syndrome are a form of ‘faster aging’ of the brain and it has been speculated that perhaps some mech- anisms may be shared. One possible shared mechanism may be deficiencies involving neurotrophin growth factors and their receptors, in particular nerve growth factor (NGF). NGF is responsible for the survival of cholinergic neurons, maintenance of the cholinergic phenotype and function of adult cholinergic neurons (Eide et al. 1993) and acute antagonism of NGF receptors in the adult rat results in cholinergic degeneration (Sofroniew et al. 1993; Debeir et al. 1999). The NGF receptor that is clearly associated with neuronal survival is termed TrkA, a receptor tyrosine kinase (Kaplan and Miller 1997). In the CNS, TrkA is expressed almost exclusively by a subset of cholinergic cortical and NB neurons (Sobreviela et al. 1994; Chao et al. 1998; Sofroniew et al. 2001). NGF is secreted by target neurons in the cortex, binds Received June 3, 2005; revised manuscript received July 22, 2005; accepted August 1, 2005. Address correspondence and reprint requests to H. Uri Saragovi, Department of Pharmacology and Therapeutics, Oncology/Cancer Cen- ter, McGill University, Lady Davis Institute-Jewish General Hospital, 3755 Cote St. Catherine, F-223, Montreal, Quebec, Canada, H3T 1E2. E-mail: Uri.Saragovi@mcgill.ca Abbreviations used: AD, Alzheimer’s disease; ChAT, choline acetyl transferase; FI, fully impaired; IR, immunoreactive; MCI, mild cognitive impairment; MI, mildly impaired; NB, nucleus basalis; NGF, nerve growth factor; UI, unimpaired. Journal of Neurochemistry , 2005, 95, 1472–1480 doi:10.1111/j.1471-4159.2005.03479.x 1472 Ó 2005 International Society for Neurochemistry, J. Neurochem. (2005) 95, 1472–1480