Alzheimer's Disease Markers in Aged ApoE-PON1 Deficient Mice

Background: Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging. Cardiovascular risk factors like hypertension and atherosclerosis increase the risk for AD. Polymorphic alleles of apolipoprotein E (ApoE) are one of the main genetic determinants of AD. Objective: Mice, double-knockout (DKO) for ApoE (major cholesterol carrier in brain) and PON1 (paroxonase1, reduces oxidative stress), showed severe age-dependent atherosclerosis of the arteries carrying blood to the brain even on normal diet. This prompted us to investigate the possibility of an AD pathology resulting from the deficiency of ApoE and the induction of oxidative stress. Methods: Atherosclerotic lesions were quantified by ImageJ. The brain hippocampus of young and old ApoE-PON1 DKO mice and control mice were harvested. RT-PCR analysis was performed for mRNA levels of AD specific markers. Blood levels of S100 calcium-binding protein B (S100B) protein were measured by ELISA. H&E as well as immunostaining was performed to detect amyloid-beta (A beta) plaques and neurofibrillary tangles (NFTs) in brain tissues. Evans blue dye was used to evaluate the vascular permeability and blood-brain barrier (BBB) dysfunction. Results: Results showed that the older DKO mice had severe carotid atherosclerosis, increased mRNA levels of AD markers in brain tissue, and elevated levels of serum S100B protein. Immunological staining confirmed the characteristics of AD. Ex-vivo imaging showed higher levels of Evans blue dye in the ApoE-PON1 DKO mice brain tissues, pointing toward impaired vasculature. Conclusion: Aged ApoE-PON1 DKO mice displaying AD specific markers along with A beta plaques, NFTs, and disrupted BBB suggests the animals are suffering from AD.