Vitamin B12 Inhibits Tau Fibrillization via Binding to Cysteine Residues of Tau

Abstract

Two mechanisms underlie the inhibitory/acceleratory action of chemical compounds on tau aggregation including the regulation of cellular kinases and phosphatases activity and direct binding to tau protein. Vitamin B12 is one of the tau polymerization inhibitors, and its deficiency is linked to inactivation of protein phosphatase 2A and subsequently hyperphosphorylation and aggregation of tau protein. Regarding the structure and function of vitamin B12 and tau protein, we assumed that vitamin B12 is also able to directly bind to tau protein. Hence, we investigated the interaction of vitamin B12 with tau protein in vitro using fluorometry and circular dichrosim. Interaction studies was followed by investigation into the effect of vitamin B12 on tau aggregation using ThT fluorescence, circular dichroism, transmission electron microscopy, and SDS-PAGE. The results indicated that vitamin B12 interacts with tau protein and prevents fibrillization of tau protein. Blocking the cysteine residues of tau confirmed the cysteine-mediated binding of vitamin B12 to tau and showed that binding to cysteine is essential for inhibitory effect of vitamin B12 on tau aggregation. SDS-PAGE analysis indicated that vitamin B12 inhibits tau aggregation and that tau oligomers formed in the presence of vitamin B12 are mostly SDS-soluble. We propose that direct binding of vitamin B12 is another mechanism underlying the inhibitory role of vitamin B12 on tau aggregation and neurodegeneration.

The TDMQ Regulators of Copper Homeostasis Do Not Disturb the Activities of Cu,Zn‐SOD, Tyrosinase, or the CoIII Cofactor Vitamin B12

“…Vitamin B12 is a corrinoid cobalt(III) complex involved in folate metabolism, and whose deficiency in neurodegenerative diseases has been reported . The vitamin B12 deficiency in the Alzheimer's brains is mostly exerted via inactivation of protein phosphatase 2 and hyperphosphorylation of tau protein . For this reason, any event possibly leading to inactivation of B12, and specially demetalation by a metal chelator must be avoided.…”

“…[9] The vitamin B12 deficiency in the Alzheimer's brains is mostly exerted via inactivation of protein phosphatase 2 and hyperphosphorylation of tau protein. [10] For this reason, any event possibly leading to inactivation of B12, and specially demetalation by a metal chelator must be avoided.…”

Proton Pump Inhibitors and Dementia: Physiopathological Mechanisms and Clinical Consequences

“…Vitamin B 12 deficiency caused by PPI use has been associated with dementia and cognitive impairment [ 62 ]. Vitamin B 12 is required for one-carbon transfer reactions such as methylation, which are needed for processing and production of nucleotides, phospholipids, and monoamine neurotransmitters [ 63 ].…”

“…Usually, vitamin B 12 removes a methyl group from tetrahydrofolate, turning it into methylcobalamin. Methylcobalamin then presents its methyl group to homocysteine, which is finally converted to methionine by methionine synthase [ 62 ]. Thus, vitamin B 12 deficiency is one of the main causes of hyperhomocysteinemia.…”

“…Among these enzymes, PP2A plays a crucial role as it is the main brain serine/threonine phosphatase and prevents tau hyperphosphorylation [ 66 ]. Decreased methylation may affect PP2A function by leading to hyperphosphorylation and aggregation of tau protein [ 62 ]. In animal models, aside from inducing tau protein hyperphosphorylation, hyperhomocysteinemia can increase A β production, while folate/vitamin B 12 supplementation may attenuate these effects [ 67 – 69 ].…”