Functional vitamin B(12) deficiency and Alzheimer disease

Area of Science:

• Neuroscience
• Biochemistry
• Vascular Biology

Background:

• Elevated total serum homocysteine is linked to atherothrombotic vascular events and neurodegenerative diseases like Alzheimer's disease (AD) and vascular dementia.
• Homocysteine is thought to exacerbate endothelial and neuronal oxidative injury in these conditions.
• Existing models do not fully explain the observed features of hyperhomocysteinemia in AD, such as the absence of macrocytic anemia.

Purpose of the Study:

• To propose a complementary model of oxidative stress-induced hyperhomocysteinemia in AD.
• To explain the role of cerebral oxidative stress in impairing homocysteine metabolism and vitamin B12 activity within neurons.
• To identify potential therapeutic strategies for addressing hyperhomocysteinemia in AD.

Main Methods:

• The study proposes a theoretical model based on existing biochemical pathways and clinical observations.
• It focuses on the interaction between cerebral oxidative stress, single-carbon metabolism, and vitamin B12.
• The model examines the oxidation of cob(I)alamin and the intraneuronal reduction of vitamin B12.

Main Results:

• Cerebral oxidative stress may oxidize cob(I)alamin, an intermediate in the methionine synthase reaction, thus hindering homocysteine metabolism.
• Oxidative stress can also impair the reduction of vitamin B12 to its active form within neurons.
• Standard pharmaceutical forms of vitamin B12 may not be effectively utilized by neurons under these pathological conditions.

Conclusions:

• A novel hypothesis suggests that impaired vitamin B12 metabolism, driven by oxidative stress, contributes to hyperhomocysteinemia in AD.
• This model accounts for specific clinical observations in AD patients, including the lack of macrocytic anemia.
• Glutathionylcobalamin is proposed as a potentially more effective therapeutic agent for treating vitamin B12-deficient hyperhomocysteinemia in AD patients.