Perinatal Lead Exposure Associated with Increased β-Amyloid in Aged Murine Brain

 

RK Morgan, EK Matei, IL Bergin, T Ishikawa, J Pan, KM Polemi, DC Dolinoy, KM Bakulski, JA Colacino

Background

Exposures to neurotoxicants, including lead (Pb), during development are suspected contributors to dementia. Pathological characteristics of dementia include β-amyloid plaques, which result from the aggregation of β-amyloid peptides and contribute to amyloid angiopathy and neuroinflammation. Here, we assess the impact of developmental Pb exposure on β-amyloid. 

Methods

Female C57/B6 mice 6 to 8 weeks of age were exposed to 32 ppm Pb or control water from two weeks prior to mating through offspring weaning, resulting in human-relevant dam blood Pb levels (10 µg/dL) . Offspring were aged to 18 months of age. The left-brain hemisphere was formalin fixed and paraffin embedded (Pb female = 10, Pb male = 10, control female = 10, control male = 11). Sections were stained with hematoxylin and eosin, Luxol Fast blue, or an antibody targeting multiple forms of β-amyloid 1-42. Cells were segmented and staining intensity assessed using QuPath. Differences in diffuse signal, positive cells per tissue area, and mineralization were calculated using a two-sided t-test (significance at p < 0.05) comparing exposed and control, stratified by sex.

Results

β-amyloid plaques were not present in any samples. Low to moderate β-amyloid immunolabeling was present diffusely across the cerebrum and thalamus and more intensely within capillary walls and mineralized thalamic foci. Mean β-amyloid intensity was higher in Pb female samples relative to control (fold change, FC: 1.26, p = 0.004). This trend was also present in male tissues (FC: 1.12) but was not statistically significant (p = 0.095). Exposed females had, on average, 320 β-amyloid positive cells per tissue versus 166 in female control (FC: 1.92, p = 0.011).  Exposed males had, on average, 469 β-amyloid positive cells per total tissue slide versus 258 in male controls (FC: 1.82, p = 0.032). 

Conclusion

Lack of β-amyloid plaques may reflect C57/B6 resistance to dementia pathology. Perinatal Pb exposure led to an increase in diffuse β-amyloid and β-amyloid-positive cells in aged murine brain. Ongoing work is quantifying the presence of other dementia hallmarks in the same tissues in C57/B6 and 5xFAD mice, which robustly present dementia hallmarks, to characterize interactions between genetic risk and exposure.