Montecinos-Oliva Carla, Arrázola Macarena S, Jara Claudia, Tapia-Rojas Cheril, Inestrosa Nibaldo C
Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular y Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile.
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor de Chile, Santiago 8580745, Chile.
Pharmaceuticals (Basel). 2020 Feb 2;13(2):24. doi: 10.3390/ph13020024.
Alzheimer's Disease (AD) is the primary cause of dementia among the elderly population. Elevated plasma levels of homocysteine (HCy), an amino acid derived from methionine metabolism, are considered a risk factor and biomarker of AD and other types of dementia. An increase in HCy is mostly a consequence of high methionine and/or low vitamin B intake in the diet. Here, we studied the effects of physiological and pathophysiological HCy concentrations on oxidative stress, synaptic protein levels, and synaptic activity in mice hippocampal slices. We also studied the in vitro effects of HCy on the aggregation kinetics of Aβ. We found that physiological cerebrospinal concentrations of HCy (0.5 µM) induce an increase in synaptic proteins, whereas higher doses of HCy (30-100 µM) decrease their levels, thereby increasing oxidative stress and causing excitatory transmission hyperactivity, which are all considered to be neurotoxic effects. We also observed that normal cerebrospinal concentrations of HCy slow the aggregation kinetic of Aβ, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ over long-term potentiation. Altogether, by studying an ample range of effects under different HCy concentrations, we report, for the first time, that HCy can exert beneficial or toxic effects over neurons, evidencing a hormetic-like effect. Therefore, we further encourage the use of HCy as a biomarker and modifiable risk factor with therapeutic use against AD and other types of dementia.
阿尔茨海默病（AD）是老年人群痴呆症的主要病因。同型半胱氨酸（HCy）是一种由甲硫氨酸代谢产生的氨基酸，血浆中HCy水平升高被认为是AD及其他类型痴呆症的一个风险因素和生物标志物。HCy升高主要是饮食中甲硫氨酸含量高和/或维生素B摄入量低所致。在此，我们研究了生理和病理生理浓度的HCy对小鼠海马切片氧化应激、突触蛋白水平和突触活性的影响。我们还研究了HCy对β淀粉样蛋白（Aβ）聚集动力学的体外效应。我们发现，生理浓度的脑脊液HCy（0.5µM）会使突触蛋白增加，而较高剂量的HCy（30 - 100µM）则会降低其水平，从而增加氧化应激并导致兴奋性传递亢进，这些都被认为是神经毒性作用。我们还观察到，正常脑脊液浓度的HCy会减缓Aβ的聚集动力学，而高浓度则会加速其聚集。最后，我们研究了HCy和HCy + Aβ对长时程增强的影响。总之，通过研究不同HCy浓度下的一系列广泛效应，我们首次报告HCy对神经元可产生有益或毒性作用，证明了一种类 hormetic 效应。因此，我们进一步鼓励将HCy用作生物标志物和可改变的风险因素，用于针对AD和其他类型痴呆症的治疗。
