Neuronal expression of F-box and leucine-rich-repeat protein 2 decreases over Braak stages in the brains of Alzheimer's disease patients.

ABSTRACT

BACKGROUND: The dysfunction of protein degradation through the ubiquitin-proteasome system is now widely accepted as one of the causes of Alzheimer's disease (AD), the pathological hallmarks of which are abnormal protein accumulation such as senile plaques and neurofibrillary tangles in the brain. OBJECTIVE: To examine the expression of F-box and leucine-rich-repeat protein 2 (FBL2), a member of the ubiquitin-protein ligase complex expected to be involved in the ubiquitin-proteasome system. METHODS AND RESULTS: We investigated the expression profile of FBL2 in the brains of AD patients by quantitative PCR and immunohistochemical analysis. In healthy subjects, the FBL2 mRNA level was very high in the brain when compared to other tissues. FBL2 immunoreactivities were detected in somata and dendrites in the neurons, but not detected in astrocytes or microglia. The FBL2 mRNA level decreased progressively in the brains of AD patients over Braak stages; this was more prominent in the temporal cortex (known to be a vulnerable region) than in the frontal cortex. Interestingly, the decrease was more severe in AD patients carrying the apolipoprotein E4 allele. The FBL2 IR also decreased over Braak stages, and was hardly detected at Braak stage 5 in both NeuN-positive and EAAC1-positive glutamatergic neurons. CONCLUSION: These results suggest that the involvement of the reduction of FBL2 level is related to AD progression.