Developmental lead exposure and the exacerbation of Alzheimer's\r\npathology: an immunological analysis

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Annalise Noelle Vonderembse (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: Early neuroimmune dysfunction may play a driving role in the etiopathology of Alzheimer's disease (AD), stemming from the hypothesis that many late-stage adult diseases have an early-life basis. Here we explore whether exposure to a known neuroimmunotoxicant during a period of developmental susceptibility in the central nervous system (CNS) parenchyma exacerbates the pathologies in an AD prone triple transgenic mouse model (3xTgAD). This "double-hit" research design is optimal for modeling the high variability in AD due to detrimental exogenous influences, rather than the minority of AD cases that have a well-defined genetic origin and regular neurodegenerative progression. We gavaged triple transgenic mice with lead acetate from postnatal day 5-15, a critical developmental window for microglia, immune cells of the CNS that are thought to play a major role in shaping the CNS. We then analyzed microglial phenotype and colocalization with amyloid-beta, the protein associated with AD senile plaques, to appropriately detect the change in pathological severity due to the intimate correlation of microglia with amyloid-beta plaques. Our data indicate early exposure to a neurotoxicant increases the number of activated microglia with age, which we hypothesize is due to either degradation of homeostatic inhibitory signaling pathways associated with early onset synaptic degeneration or over-burdened microglial phagocytic load. Furthmore, microglial activation states differed between genders and fluctuated with age, suggesting a sex-specific component to AD pathology and potential correlation of neurodegenerative diseases with hormone receptors in the sexual differentiation of the developing brain.

Additional Information

Publication

Thesis

Language: English

Date: 2023

Subjects

Toxicology;Neuroscience;Developmental biology;Alzheimer's disease;Developmental immunotoxicology;Microglia;Neurotoxicology;Biology, Neuroscience

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