Circulating and Extracellular Vesicles Levels of N-(1-Carboxymethyl)-L-Lysine (CML) Differentiate Early to Moderate Alzheimer's Disease

Background: Both advanced glycation end products (AGEs) N-(1-carboxymethyl)-L-lysine (CML) and pentosidine were found in the brain from Alzheimer's disease (AD) patients and were associated with the neuropathological hallmarks of AD. In AD patients, the circulating level of both AGEs remains unknown. Moreover, their levels in peripheral extracellular vesicles (EVs) and their association with AD remain to be determined. Finally, it is not known if neuronal cells can release AGEs via EVs and propagate AGEs. Objective: To determine the levels of circulating CML and pentosidine during the progression of AD. Moreover, their levels in circulating EVs were determined and their association with the clinical cognitive scores were analyzed. Finally, we have studied the possibility that neuronal cells eliminate and transfer these AGEs through EVs. Methods: CML and pentosidine levels were measured in serum and in circulating EVs. Released-EVs from SK-N-SH neuronal cells were isolated and CML levels were also determined. Results: The levels of CML in albumin-free serum proteins were higher in the early stage of AD while the levels of pentosidine remained unchanged. In contrast, the levels of CML in the EVs were lower in the moderate stage of AD. Interestingly, the levels of CML in serum were negatively correlated with the clinical cognitive scores MMSE and MoCA. For the first time, we were able to demonstrate that CML was present in EVs released from neuronal cells in culture. Conclusion: Peripheral and circulating EVs levels of CML can differentiate early to moderate AD. In the brain, neuronal CML can propagate from cells-to-cells via EVs.