Background: Impaired axonal transport may contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD) and Down syndrome (DS). Axonal transport is a complex process in which specific motor proteins move cargoes to and from neuronal cell bodies and their processes. Inconsistent reports point to the changes in AD in the levels of the classical anterograde motor protein kinesin family member 5 (KIF5) and the primary neuronal KIF regulator kinesin light chain 1 (KLC1), raising the possibility that anterograde transport is compromised in AD.
Methods and materials: To address inconsistencies and determine if the shared pathologies in AD and elderly DS subjects with dementia (AD in DS; AD-DS) extend to the changes in KIF5 and KLC1, we measured the levels of all the three KIF5 family members and KLC1 in the AD and AD-DS frontal cortex and AD temporal cortex and cerebellum in samples taken with a short postmortem interval. To support future studies to explore the cell biological basis for any changes detected, we also examined the levels of these proteins in the brains of young and aged adult mice in the Dp (16)1Yey/+ (Dp16) mouse model of DS and J20 mouse model of AD.
Results: There were no changes in comparison with controls in KIF5 family members in either the AD or AD-DS samples when normalized to either β-actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, however, samples from control brains as well as from AD and AD-DS demonstrated strong positive correlations between the levels of KIF5 family members, suggesting positive co-regulated expression. Importantly, while earlier reports pointed to a negative correlation between the levels of the amyloid precursor protein (APP) and KIF5A levels, we found the opposite to be true in AD-DS; this was especially striking given triplication of the APP gene, with increased APP protein levels. AD and control samples showed positive correlations between fl-hAPP and KIF5 members, but they were less consistent. In contrast to the findings for KIF5, the levels of KLC1 were downregulated in the frontal cortex of both AD and AD-DS brains; interestingly, this change was not seen in the AD temporal cortex or cerebellum. As postmortem interval has a negative effect on the levels of KLC1, but not KIF5 members, we analyzed a subset of samples with a very short postmortem interval (PMI) (≤ 6 h), a PMI that was not significantly correlated with the levels of KLC1 in either AD or AD-DS samples; we confirmed the presence of a statistically significant reduction of KLC1 in AD and AD-DS brains as compared with control brains. Studies comparing Dp16 to its euploid control recapitulated human studies in demonstrating no change in KIF5 levels and a positive correlation between the levels of KIF5 family members. J20 mice also showed normal KIF5 levels. However, unlike the AD and AD-DS frontal cortex, KLC1 levels were not reduced in the brains of Dp16 or J20 mice.
Conclusion: These data point to significant reductions in KLC1 in AD and AD-DS. In so doing, they raise the possibility of compromised KLC1-mediated axonal transport in these conditions, a posit that can now be pursued in model systems in which KLC1 expression is reduced.
Keywords: APP; Alzheimer’s disease; Axonal transport; Down syndrome; Dp16; KIF5; KLC1.