Abstract
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.
Highlights
Homocysteine (HCy) is a sulfur-containing amino acid and a byproduct of methyl-transfer reactions due to methionine metabolism [1]
Our results show that: (1) High HCy concentrations cause an increase in oxidative stress, (2) HCy induces differential changes in the levels of pre- and post-synaptic proteins, (3) high HCy concentrations induce a toxic overactivation of excitatory transmission in the CA1 hippocampal region, and (4) low HCy concentrations cause slower Aβ40 aggregation, whereas elevated HCy increases the aggregation kinetics
We studied the effects of oxidative stress indicators after acute HCy treatment (1 h) of hippocampal slices from two-month-old wild-type mice
Summary
Homocysteine (HCy) is a sulfur-containing amino acid and a byproduct of methyl-transfer reactions due to methionine metabolism [1]. Levels of homocysteine are controlled mainly by diet, through the intake of methionine-rich and B-vitamin-family-rich (B6, folic acid and B12) food [2]. There is an increase in total plasma HCy levels within a range that is considered normal [3]. Under age-associated pathological conditions, such as neurogenerative disease, there is an abnormal increase in the total HCy levels found in plasma and cerebrospinal fluid (CSF) [3,4]. Total plasma HCy concentrations in the range of 5–15 μM are considered to be normal, while 15–30 μM HCy is considered mild, and 30–100 μM is moderate. Levels over 100 μM reflect severe homocysteinemia, a condition called hyperhomocysteinemia (HHCy) [5]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
