Research

LaDu Lab Mission:

1. INVESTIGATE: the interaction of apoE and Aβ as modulated by universal biological variables for AD (age, APOE, and sex).

2. INNOVATE: predictive biomarkers and novel preclinical drug trials based on the universal biological variables.

3. EDUCATE: the next generation of exceptional scientists and physicians.

1. INVESTIGATE: the interaction of apoE and Aβ as modulated by universal biological variables.

Meet the EFADs: the novel AD transgenic mouse model

Progression of Pathology by Region in EFAD Mice

  • Progression of pathology in the EFAD mouse brain starts in the subiculum, hippocampus, proceeds to the cortex, and finally to the thalamus.

Synergistic Effects of Sex + APOE4 on Pathology in EFAD Mice

  • Aβ deposition and neuroinflammation in 8 month E4FAD brains: female > male.

2. INNOVATE: predictive biomarkers and novel preclinical drug trials based on the universal biological variables (age, APOE, sex).

The Road From EFAD Mice to Precision AD Therapeutics: Stratification is Fundamental

  • EFAD are a relevant preclinical AD mouse model.

  • We can use this EFAD mice to validate biomarkers and screen therapeutics for the prevention and treatment of AD.

Potential Human Biomarkers: Plasma oAβ

University of Wisconsin-Madison Alzheimer’s Disease Research Center (ADRC) n= 200

  • Plasma oAβ levels are higher in AD vs. control subjects.

  • Stratification by genotype shows this increase is driven by APOE4/4 subjects.

  • Stratification by sex shows the increase is driven by females.

  • Stratification by sex within genotype shows females > males in E3/E3s and E4/E4s and male E4/E4s > male E3/E3s.

Potential Therapeutics for APOE4-modulated AD Pathology

The therapeutics we are currently testing in the EFAD mice:

  • Target apoE lipidation

  • Target estrogen receptors

  • Target neuroinflammation

Featured Project

Effect of sexual differentiation on APOE-modulated AD pathology

Hypothesized Relationship Between APOE, sex and AD risk

Sexual Differentiation of the Rodent Brain

  • Sex differences in the brain are established during a critical period.

  • Feminization of the brain proceeds in the absence of exposure to elevated gonadal steroids.

  • Masculinization of the brain occurs when fetal testes begin production of androgens at the beginning of the critical period.

Experimental Design

Given that female sex increases risk for developing AD, we want to examine how sexual differentiation can modify pathology in EFAD mice. Hormone injections peri- and postnatally may alter sexual differentiation of EFAD brains.

  • Feminized males-male mice will receive perinatal (mom) and postnatal (pups) flutamide (anti-androgen) injections.

  • Masculinized females-female mice will receive perinatal (mom) and postnatal (pups) testosterone injections.

  • Mice will be gonadectomized.

  • Feminized males will receive testosterone capsules and masculinized females will receive estradiol capsules.

  • Mice will perform behavioral tests and be sacrificed.

  • Biochemical analysis will be done on brain tissue and plasma.

3. EDUCATE: the next generation of exceptional scientists and physicians.

Helena Xeros

Degree: BS Biology and Philosophy of Science, Washington University in St. Louis

Program: MD/MS Program for Clinical Translational Research

Thesis Title: Sex differences in the relationship between APOE and AD: Role of sexual differentiation.

New members (babies) Party 2021