Altered NCAM Expression Associated with the Cholinergic System in Alzheimer's Disease

Article type: Research Article

Authors: Aisa, Bárbara^a | Gil-Bea, Francisco J.^a | Solas, Maite^a | García-Alloza, Mónica^b | Chen, Christopher P.^c | Lai, Mitchell K.^{c; d} | Francis, Paul T.^e | Ramírez, María Javier^{a; *}

Affiliations: [a] Department of Pharmacology, School of Medicine, Center for Applied Medical Research, University of Navarra, Pamplona, Spain | [b] Division of Physiology, College of Medicine, University of Cadiz, Spain | [c] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [d] Dementia Research Laboratory, Department of Clinical Research, Singapore General Hospital, Singapore | [e] Wolfson Centre for Age-Related Diseases, King's College London, UK

Correspondence: [*] Correspondence to: Dr. María J. Ramírez, Center for Applied Medical Research, Department of Pharmacology, School of Medicine, University of Navarra, C/ Irunlarrea, 1, 31008 Pamplona, Spain. Tel.: +34 948425600; Fax: +34 948425649; E-mail: mariaja@unav.es.

Note: [] Handling Associate Editor: Christoph Laske

Abstract: Neurotransmitter system dysfunction and synapse loss have been recognized as hallmarks of Alzheimer's disease (AD). Our hypothesis is that specific neurochemical populations of neurons might be more vulnerable to degeneration in AD due to particular deficits in synaptic plasticity. We have studied, in postmortem brain tissue, the relationship between levels of synaptic markers (NCAM and BDNF), neurochemical measurements (cholinacetyltransferase activity, serotonin, dopamine, GABA, and glutamate levels), and clinical data (cognitive status measured as MMSE score). NCAM levels in frontal and temporal cortex from AD patients were significantly lower than control patients. Interestingly, these reductions in NCAM levels were associated to an ApoE4 genotype. Levels of BDNF were also significantly reduced in both frontal and temporal regions in AD patients. The ratio between plasticity markers and neurochemical measurements was used to study which of the neurochemical populations was particularly associated to plasticity changes. In both the frontal and temporal cortex, there was a significant reduction in the ChAT/NCAM ratio in AD samples compared to controls. None of the ratios to BDNF were different between control and AD samples. Furthermore, Pearson's product moment showed a significant positive correlation between MMSE score and the ChAT/NCAM ratio in frontal cortex (n=19; r=0.526*; p=0.037) as well as in temporal cortex (n=19; r=0.601*; p=0.018) in AD patients. Altogether, these data suggest a potential involvement of NCAM expressing neurons in the cognitive deficits in AD.

Keywords: BDNF, ChAT, cognitive deficits, frontal cortex (BA10), MMSE, plasticity, temporal cortex (BA20)

DOI: 10.3233/JAD-2010-1398

Journal: Journal of Alzheimer's Disease, vol. 20, no. 2, pp. 659-668, 2010