Homocysteine, another risk factor for Alzheimer disease, impairs apolipoprotein E3 function

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Apolipoprotein E (apoE) ε4 and hyperhomocysteinemia are established risk factors for Alzheimer disease (AD).
• ApoE3 dimerization via cysteine residues enhances its function in High-Density Lipoprotein (HDL) generation.
• Homocysteine (Hcy) possesses a thiol group, suggesting potential interference with protein disulfide bonds.

Purpose of the Study:

• To investigate whether homocysteine (Hcy) interferes with apolipoprotein E3 (apoE3) dimerization.
• To determine if Hcy impairs apoE3 function in HDL generation.
• To explore a potential shared mechanism between apoE4 and hyperhomocysteinemia in AD pathogenesis.

Main Methods:

• In vitro experiments assessing Hcy's effect on apoE3 dimerization and HDL generation.
• Western blot analysis of cerebrospinal fluid (CSF) from hyperhomocysteinemic patients and controls.
• In vivo studies using apoE3 knock-in mice with induced hyperhomocysteinemia.

Main Results:

• Homocysteine (Hcy) was found to inhibit apoE3 dimerization.
• Hcy significantly reduced apoE3-mediated HDL generation to levels comparable to apoE4.
• CSF analysis revealed lower apoE3 dimer ratios in hyperhomocysteinemic patients.
• Brain homogenates from Hcy-treated mice showed decreased apoE3 dimer levels.

Conclusions:

• Homocysteine (Hcy) impairs apoE3 function by inhibiting its dimerization, mimicking the effect of the apoE4 risk factor.
• Reduced HDL generation due to hyperhomocysteinemia may represent a common pathway accelerating Alzheimer disease (AD) pathogenesis.
• These findings highlight a novel link between metabolic factors and AD risk through apoE function and HDL metabolism.