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Open AccessArticle

Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation

1
Centro de Envejecimiento y Regeneración (CARE); Departamento de Biología Celular y Molecular; Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331150, Chile
2
Center for Integrative Biology, Faculty of Sciences, Universidad Mayor de Chile, Santiago 8580745, Chile
3
Laboratory of Neurobiology of Aging, Centro de Biología Celular y Biomedicina (CEBICEM), Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago 7510156, Chile
4
Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, Punta Arenas 6213515, Chile
*
Authors to whom correspondence should be addressed.
Pharmaceuticals 2020, 13(2), 24; https://doi.org/10.3390/ph13020024
Received: 24 November 2019 / Revised: 13 January 2020 / Accepted: 28 January 2020 / Published: 2 February 2020
(This article belongs to the Special Issue Therapeutics Agents for Neural Repair)
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 Aβ40. 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 Aβ40, whereas high concentrations accelerate its aggregation. Finally, we studied the effects of HCy and HCy + Aβ42 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. View Full-Text
Keywords: Aβ oligomers; Alzheimer’s disease; excitotoxicity; hyperhomocysteinemia; homocysteine; hormesis; methionine; neurodegenerative diseases; oxidative stress Aβ oligomers; Alzheimer’s disease; excitotoxicity; hyperhomocysteinemia; homocysteine; hormesis; methionine; neurodegenerative diseases; oxidative stress
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MDPI and ACS Style

Montecinos-Oliva, C.; Arrázola, M.S.; Jara, C.; Tapia-Rojas, C.; Inestrosa, N.C. Hormetic-Like Effects of L-Homocysteine on Synaptic Structure, Function, and Aβ Aggregation. Pharmaceuticals 2020, 13, 24.

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