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

Abstract

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.

Meta‐analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

“…Combining results together in one comparison shows on which markers and brain areas research has focused and which markers and brain areas are underrepresented in the overview (Table 2). Employing the SMD allowed us to pool 67 different synaptic markers into a single overall database for comparison [19-21, 52, 55, 63-65, 67, 72, 77, 78, 80, 85, 86, 88-123]. Irrespective of the brain area these synaptic markers can be divided into 28 pre-synaptic markers in 10 functional categories, 30 postsynaptic markers in 8 functional categories, and 9 markers in 6 functional categories without specific pre- or postsynaptic localization (Table 2).…”

Inverse relationship between Alzheimer’s disease and cancer, and other factors contributing to Alzheimer’s disease: a systematic review

“…AD is also associated with low levels of BDNF in temporal and frontal brain regions [57]. NCAM is also involved in inducing neurite outgrowth via FGFR and also acts on other signaling pathways.…”

Genome-wide pathway analysis of memory impairment in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort implicates gene candidates, canonical pathways, and networks

“…Genetic variants of NCAMs have also been associated with CSF biomarkers for AD (Han et al 2010), and cell adhesion molecule pathways have exhibited enrichment in a GWA-based pathway analysis of AD susceptibility (Liu et al 2012). In addition, expression of NCAMs in cholinergic neurons appears to increase susceptibility to AD-related neurodegeneration (Aisa et al 2010), and there is emerging evidence of interactions among NCAMs, the MAPK pathway, and amyloid precursor protein (Chen and Dou 2012). More broadly, these findings suggest a prominent role for cell adhesion pathways in maintaining the processes of synaptic plasticity that are believed to underlie learning and memory (Ho et al 2011).…”