Amino-Terminal beta-Amyloid Antibody Blocks beta-Amyloid-Mediated Inhibition of the High-Affinity Choline Transporter CHT

作者：Cuddy Leah K; Seah Claudia; Pasternak Stephen H; Rylett R Jane^*

来源：Frontiers in Molecular Neuroscience, 2017, 10: 361.

DOI：10.3389/fnmol.2017.00361

• protein trafficking
• cholinergic
• beta-amyloid
• Alzheimer's disease

Alzheimer's disease (AD) is a common age-related neurodegenerative disorder that is characterized by progressive cognitive decline. The deficits in cognition and attentional processing that are observed clinically in AD are linked to impaired function of cholinergic neurons that release the neurotransmitter acetylcholine (ACh). The high-affinity choline transporter (CHT) is present at the presynaptic cholinergic nerve terminal and is responsible for the reuptake of choline produced by hydrolysis of ACh following its release. Disruption of CHT function leads to decreased choline uptake and ACh synthesis, leading to impaired cholinergic neurotransmission. We report here that cell-derived beta-amyloid peptides (A beta) decrease choline uptake activity and cell surface CHT protein levels in SH-SY5Y neural cells. Moreover, we make the novel observation that the amount of CHT protein localizing to early endosomes and lysosomes is decreased significantly in cells that have been treated with cell culture medium that contains A beta peptides released from neural cells. The A beta-mediated loss of CHT proteins from lysosomes is prevented by blocking lysosomal degradation of CHT with the lysosome inhibitor bafilomycin A1 (BafA(1)). BafA(1) also attenuated the A beta-mediated decrease in CHT cell surface expression. Interestingly, however, lysosome inhibition did not block the effect of A beta on CHT activity. Importantly, neutralizing A beta using an anti-A beta antibody directed at the N-terminal amino acids 1-16 of A beta, but not by an antibody directed at the mid-region amino acids 22-35 of A beta, attenuates the effect of A beta on CHT activity and trafficking. This indicates that a specific N-terminal A beta epitope, or specific conformation of soluble A beta, may impair CHT activity. Therefore, A beta immunotherapy may be a more effective therapeutic strategy for slowing the progression of cognitive decline in AD than therapies designed to promote CHT cell surface levels.

• 出版日期2017-11-7
• 单位西北大学