P001 - GENOME-WIDE ASSOCIATION STUDIES, FUNCTIONAL GENOMICS AND CELL BIOLOGY IDENTIFY TBC1D5 AS AN ALZHEIMER’S DISEASE-RISK GENE AND UNCOVER ITS ROLE IN OAΒ CLEARANCE.
Abstract
Aims
The prevalence of Alzheimer’s disease (AD) along with its social and economic burden continues to rise worldwide. Increasing evidence points towards smaller, pre-fibrillary aggregates, known as beta-amyloid oligomers (oAβ), as the primary cause of disease. We identified TBC1D5 as an AD risk gene from multiple resampled GWAS in the Korean population followed by confirmational functional genomic screening in a Drosophila AD model. Further, we investigated the role of this key regulator of intracellular trafficking and vesicle transport in the clearance of oAβ in differentiated neuron-like cells.
Methods
We established a stable cell line lacking TBC1D5 by selectively inhibiting the human orthologue of this endocytic gene using siRNA in differentiated neuron-like SH-SY5Y cells. We then investigated the effect of TBC1D5 knockdown on oAβ uptake, processing and clearance after 3, 24 and 48 hours post-treatment with oAβ.
Results
The levels of TBC1D5 are significantly reduced in the cortex of human AD patients’ brains compared to that of age-matched controls and is associated with temporal lobe atrophy. Knockdown of TBC1D5 also increases oAβ accumulation in neuronal-like cells, decreases clearance of oAβ internalised from extracellular milieu and increases Aβ-induced cytotoxicity.
Conclusions
Our results suggest that endocytosis is a major cellular pathway associated with AD, and that down-regulation of molecular components of endocytic machinery may be involved in the pathological mechanisms underlying AD. Modulators of endocytic proteins, like TBC1D5, may serve as effective therapeutic targets to enhance the proper recycling and clearance of toxic oAβ to slow down disease progression.
