N‐homocysteinylation of tau and MAP1 is increased in autopsy specimens of Alzheimer's disease and vascular dementia

Abstract

The pathomechanisms that associate a deficit in folate and/or vitamin B12 and the subsequent hyperhomocysteinemia with pathological brain ageing are unclear. We investigated the homocysteinylation of microtubule‐associated proteins (MAPs) in brains of patients with Alzheimer's disease or vascular dementia, and in rats depleted in folate and vitamin B12, Cd320 KO mice with selective B12 brain deficiency and H19‐7 neuroprogenitors lacking folate. Compared with controls, N‐homocysteinylated tau and MAP1 were increased and accumulated in protein aggregates and tangles in the cortex, hippocampus and cerebellum of patients and animals. N‐homocysteinylation dissociated tau and MAPs from β‐tubulin, and MS analysis showed that it targets lysine residues critical for their binding to β‐tubulin. N‐homocysteinylation increased in rats exposed to vitamin B12 and folate deficit during gestation and lactation and remained significantly higher when they became 450 days‐old, despite returning to normal diet at weaning, compared with controls. It was correlated with plasma homocysteine (Hcy) and brain expression of methionine tRNAsynthetase (MARS), the enzyme required for the synthesis of Hcy–thiolactone, the substrate of N‐homocysteinylation. Experimental inactivation of MARS prevented the N‐homocysteinylation of tau and MAP1, and the dissociation of tau and MAP1 from β‐tubulin and PSD95 in cultured neuroprogenitors. In conclusion, increased N‐homocysteinylation of tau and MAP1 is a mechanism of brain ageing that depends on Hcy concentration and expression of MARS enzyme. Its irreversibility and cumulative occurrence throughout life may explain why B12 and folate supplementation of the elderly has limited effects, if any, to prevent pathological brain ageing and cognitive decline. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Homocysteine aggravates DNA damage by impairing the FA/Brca1 Pathway in NE4C murine neural stem cells

“…N-homocysteinylation is deleterious to protein structure, interaction and function [51]. HHcy also appears to exacerbate the effects of other factors implicated in Alzheimer's disease pathology, such as increasing N-homocysteinylated levels of tau and Aβ [4,21]. Thus, the inhibitory effect of Hcy on monoubiquitination of Fanci and Fancd2 in our study may be attributed to N-homocysteinylation.…”

“…HHcy, a medical condition of elevated Hcy concentration in the plasma, usually defined as > 15 μM 3 , is recognized as a biomarker of several cardiovascular and neurological disorders 8 . HHcy can be caused by a high Met and/or low methyl-donor diet in animal models 4 , 41 . Recently, researchers showed that Hcy administration by tail vein injection could also induce HHcy in rats 42 .…”

“…During neurodevelopment, the rapid cellular proliferation can lead to replication-induced DNA damage [20]. In mature brains, neural cells are also prone to DNA damage caused by metabolites including oxygen free radicals, homocysteine and amyloid β-peptide (Aβ) [4,17,19,21]. Failure to effectively overcome DNA damage results in damage accumulation, mitotic catastrophe, chromosomal rearrangements, and cell death.…”

“…Homocysteine (Hcy) is a non-protein amino acid, formed by methionine (Met) derived from the diet and secreted during metabolism [1]. An elevated level of Hcy in the blood results in hyperhomocysteinemia (HHcy) and is closely associated with some neurodegenerative diseases, including dementia, Alzheimer's disease and Parkinson's disease [2][3][4][5]. The deleterious influences of HHcy have also been reported in the developing central nervous system (CNS) [1,6].…”

Hydrogen Sulfide Inhibits Homocysteine-Induced Neuronal Senescence by Up-Regulation of SIRT1

“…Our previous studies have demonstrated that H 2 S has a protective effect against Hcy-evoked neurotoxicity [20,[24][25][26]. Considering the cellular senescence is prominent in the neurotoxicity of Hcy [3,[27][28][29], the present work was designed to explore whether the protection of H2S against the neurotoxicity of Hcy is associated with regulating neuronal senescence.…”