Abstract
Background: Early disturbances in axonal transport, before the onset of gross neuropathology, occur in a spectrum of neurodegenerative diseases including Alzheimer’s disease. Kinesin superfamily motor proteins (KIFs) are responsible for anterograde protein transport within the axon of various cellular cargoes, including synaptic and structural proteins. Dysregulated KIF expression has been associated with AD pathology and genetic polymorphisms within kinesin-light chain-1 (KLC1) have been linked to AD susceptibility. We examined the expression of KLC1 in AD, in relation to that of the KLC1 motor complex (KIF5A) and to susceptibility genotypes. Methods: We analysed KLC1 and KIF5A gene and protein expression in midfrontal cortex from 47 AD and 39 control brains. Results: We found that gene expression of both KIF5A and KLC1 increased with Braak tangle stage (0-II vs III-IV and V-VI) but was not associated with significant change at the protein level. We found no effect of KLC1 SNPs on KIF5A or KLC1 expression but KIF5A SNPs that had previously been linked to susceptibility in multiple sclerosis were associated with reduced KIF5A mRNA expression in AD cortex. Conclusions: Future in vitro and in vivo studies are required to understand the cause of upregulated KIF5A and KLC-1 gene expression in AD and any potential downstream consequences on pathogenesis, including any contribution of genetic polymorphisms within the KIF5A gene locus.
Highlights
Over 90% of Alzheimer’s disease (AD) cases are sporadic rather than attributable to a single gene mutation
We found that gene expression of both KIF5A and kinesin-light chain-1 (KLC1) increased with Braak tangle stage (0-II vs III-IV and V-VI) but was not associated with significant change at the protein level
We found no effect of KLC1 single nucleotide polymorphisms (SNPs) on KIF5A or KLC1 expression but KIF5A SNPs that had previously been linked to susceptibility in multiple sclerosis were associated with reduced KIF5A mRNA expression in AD cortex
Summary
Over 90% of Alzheimer’s disease (AD) cases are sporadic rather than attributable to a single gene mutation In these cases, as for many other sporadic adult-onset neurodegenerative diseases, the pathological changes are likely to be caused by a combination of environmental and genetic factors that activate variably independent pathogenic pathways that increase neuronal vulnerability to damage and death. A crucial step in this transition from potentially reversible to irreversible disease is the disruption in axonal delivery of membrane-bound organelles from the neuronal soma to the synapse. The development of such disruption has been recognised pathologically in brain tissue, including in AD8, by the formation of axonal swellings at an early stage in the disease process. We examined the expression of KLC1 in AD, in relation to that of the KLC1 motor complex (KIF5A) and to susceptibility genotypes
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