Date Published: June 1, 2018
Publisher: BioMed Central
Author(s): Madhurima Chatterjee, Marta Del Campo, Tjado H. J. Morrema, Matthijs de Waal, Wiesje M. van der Flier, Jeroen J. M. Hoozemans, Charlotte E. Teunissen.
Synaptic and axonal loss are two major mechanisms underlying Alzheimer’s disease (AD) pathogenesis, and biomarkers reflecting changes in these cellular processes are needed for early diagnosis and monitoring the progression of AD. Contactin-2 is a synaptic and axonal membrane protein that interacts with proteins involved in the pathology of AD such as amyloid precursor protein (APP) and beta-secretase 1 (BACE1). We hypothesized that AD might be characterized by changes in contactin-2 levels in the cerebrospinal fluid (CSF) and brain tissue. Therefore, we aimed to investigate the levels of contactin-2 in the CSF and evaluate its relationship with disease pathology.
Contactin-2 was measured in CSF from two cohorts (selected from the Amsterdam Dementia Cohort), comprising samples from controls (cohort 1, n = 28; cohort 2, n = 20) and AD (cohort 1, n = 36; cohort 2, n = 70) using an analytically validated commercial enzyme-linked immunosorbent assay (ELISA). The relationship of contactin-2 with cognitive decline (Mini-Mental State Examination (MMSE)) and other CSF biomarkers reflecting AD pathology were analyzed. We further characterized the expression of contactin-2 in postmortem AD human brain (n = 14) versus nondemented controls (n = 9).
CSF contactin-2 was approximately 1.3-fold reduced in AD patients compared with controls (p < 0.0001). Overall, contactin-2 levels correlated with MMSE scores (r = 0.35, p = 0.004). We observed that CSF contactin-2 correlated with the levels of phosphorylated tau within the control (r = 0.46, p < 0.05) and AD groups (r = 0.31, p < 0.05). Contactin-2 also correlated strongly with another synaptic biomarker, neurogranin (control: r = 0.62, p < 0.05; AD: r = 0.60, p < 0.01), and BACE1, a contactin-2 processing enzyme (control: r = 0.64, p < 0.01; AD: r = 0.46, p < 0.05). Results were further validated in a second cohort (p < 0.01). Immunohistochemical analysis revealed that contactin-2 is expressed in the extracellular matrix. Lower levels of contactin-2 were specifically found in and around amyloid plaques in AD hippocampus and temporal cortex. Taken together, these data reveal that the contactin-2 changes observed in tissues are reflected in CSF, suggesting that decreased contactin-2 CSF levels might be a biomarker reflecting synaptic or axonal loss. The online version of this article (10.1186/s13195-018-0383-x) contains supplementary material, which is available to authorized users.
Alzheimer’s disease (AD) is the major cause of dementia worldwide . AD patients are characterized by high levels of cerebrospinal fluid (CSF) tau reflecting tangle pathology whereas the underlying amyloid beta (Aβ) plaque pathology is mirrored by decreased levels of Aβ42 in the CSF . However, about 30% of the cognitively normal elderly also have an AD CSF biomarker profile, making AD diagnosis complex [3, 4]. Thus, additional biomarkers are needed for a better diagnosis. Furthermore, synaptic dysfunction [5, 6] and axonal loss  are early events in the pathogenesis of AD [6, 8–12]. Synapse loss has been suggested to be related more strongly with cognitive impairment than plaque or tangle pathology [13–16]. Therefore, biomarkers reflecting these changes might be useful to support early diagnosis and prognosis of AD. Several synaptic biomarkers in CSF have been identified, such as neurogranin [17, 18], synaptotagmin , synaptosomal-associated protein (SNAP)-25 , and Ras-related protein (Rab)-3A . Neurogranin is a promising synaptic biomarker which has been found to be specifically increased in AD [17, 18, 21]. So far, there are no established biomarkers for axonal loss specific for AD. Increased tau level has been related with axonal loss , but increased tau is a rather unspecific finding indicating neurodegeneration .
The main finding of this study is that the levels of the synaptic/axonal protein contactin-2 in the CSF differs between AD patients and controls, and is associated with other biomarkers, particularly tTau, pTau, Aβ40, BACE1, and neurogranin. Moreover, we also performed characterization of this protein in postmortem human brain tissue and found areas with reduced contactin-2 expression in and around fibrillar neuritic plaques.
In summary, this study reveals a reduction in the axonal and synaptic protein contactin-2 in two CSF cohorts and postmortem tissue, and indicates the potential of this protein as a novel AD CSF biomarker reflecting synaptic/axonal dysfunction. Future studies should investigate how contactin-2 is changed during the course of AD in a longitudinal study design with larger patient cohorts. In addition, studies revealing a mechanistic relation between contactin-2, Aβ, and tau are required to understand the bigger picture of the cell signaling pathway underlying AD pathogenesis and to open new leads for therapy development.