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.

Analysis of EFAD Mice

CNS ApoE-containing Lipoproteins

  • ApoE is an apolipoprotein, the protein component of lipoproteins.

  • ApoE is the only apolipoprotein expressed in the brain.

  • In the brain, apoE-containing lipoproteins are produced by glial cells.

The Proximal Neurotoxin: Soluble oAβ

  • AD is diagnosed postmortem by amyloid plaques and neurofibrillary tangles.

  • can aggregate to form fibrils that further aggregate to form amyloid plaques.

  • There is a poor correlation between amyloid and dementia.

  • Oligomers of Aβ (oAβ) are likely the proximal neurotoxins.

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 APOE4 + Sex on Pathology in EFAD Mice

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

The Effects of Age, APOE, Sex on Neuroinflammation and Aβ Deposition in EFAD Mice

  • Neuroinflammation (GFAP) increases with age, E4FAD > E3FAD, and Females > Males.

  • Aβ deposition (MOAB2) increases with age, E4FAD > E3FAD, and Females > Males.

Survival Curves of Human vs. EFAD (Kaplan-Meier Curves)


  • Expression of the E4 allele increases AD risk in humans, indicating that E4 is dominant over E3.

  • Consistent with humans, APOE4 genotype is dominant over APOE3 in EFAD mice, decreasing survival in E4FADs.

  • Additionally, female sex is dominant over male sex in EFAD mice.

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

Stratification is Fundamental

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.

Plasma Lipoprotein

Higgins, Pharmacol Biochem & Beh, 1997




  • Plasma lipoprotein profiles are intact lipoprotein particles that are eluted from largest to smallest (Chylomicrons > VLDL > LDL > HDL-2 > HDL-3 > free proteins) using size exclusion chromatography columns.

  • The plasma lipoprotein profile, the signature of peripheral lipid transport, is age- and APOE genotype dependent.

The Road From EFAD Mice to Precision AD Therapeutics

EFAD mice can be stratified by APOE and sex to find precise AD therapeutics




  • EFAD are a relevant preclinical AD mouse model.

  • We can use this EFAD mouse model to screen therapeutics for the prevention and treatment of AD.

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 Projects

How does estrogen-based therapy effect behavior and pathology in female (♀) EFAD mice?

AD risk in female APOE3/4 is increased 2-4 fold while the risk in males is unchanged. Can we replicate these results in our EFAD mice?

Farrer, JAMA, 1997

Experimental Design

In order to target estrogen receptors as a therapeutic, we looked at menopause which is often accompanied by a depletion of naturally produced estrogen. In mice, we can mimic early and normal menopause by performing ovariectomies.

  • Mice will be ovariectomized (OVX) at 4M (early OVX) and 8M (normal OVX).

  • Mice will be treated with various estrogen therapy treatments.

  • Mice will perform behavioral tests and be sacrificed.

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

Treatments:

  • Tx1: High Estradiol (E2)

  • Tx2: ERβ agonist (proprietary)

  • Tx3: Raloxifene mixed ERα/β (commercial)

    • Most widely prescribed selective estrogen receptor modulator (SERM) for menopausal symptoms.

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.

Pictured: Graduating Seniors 2019, Deebika Balu, Ana Valencia Olvera, Juan Maldonado Weng, Mary Jo LaDu

Students in the LaDu lab attend various conferences and competitions each year