Gene-environment interaction between lead and Apolipoprotein E4 causes cognitive behavior deficits in mice

Area of Science:

• Neuroscience
• Toxicology
• Genetics

Background:

• Alzheimer's disease (AD) involves cognitive decline, with environmental factors and gene-environment interactions (GXE) potentially influencing risk.
• Direct evidence for GXE in AD pathogenesis, particularly concerning environmental toxins like lead, remains limited.

Purpose of the Study:

• To investigate the GXE between lead exposure and the Apolipoprotein E4 (ApoE4) allele on cognitive behavior and adult hippocampal neurogenesis.
• To determine if lead exposure differentially impacts cognitive function and neural development in mice with different Apolipoprotein E (ApoE) genotypes.

Main Methods:

• Transgenic mice expressing human ApoE4 (ApoE4-KI) or ApoE3 (ApoE3-KI) were exposed to lead acetate in drinking water for 12 weeks.
• Cognitive behaviors, including contextual fear memory, spontaneous alternation, and spatial working memory, were assessed.
• Adult hippocampal neurogenesis was analyzed in a separate cohort to explore underlying mechanisms.

Main Results:

• Lead exposure significantly impaired contextual fear memory and spontaneous alternation, most notably in lead-treated ApoE4-KI female mice.
• All lead-exposed mice showed persistent spatial working memory deficits, with ApoE4-KI mice exhibiting earlier onset, especially females.
• Lead exposure selectively impaired the maturation and differentiation of adult-born hippocampal neurons in ApoE4-KI females.

Conclusions:

• GXE between lead and ApoE4 may contribute to cognitive impairment, potentially through impaired adult hippocampal neurogenesis.
• These findings highlight the role of GXE and sex differences in Alzheimer's disease risk and progression.