Assessing the Role of Amyloid Beta in Alzheimer's Disease Using the 5XFAD and TgSwDI Transgenic Mouse Strains

Abstract

The Amyloid Cascade theory of Alzheimer's disease (AD) states that formation and accumulation of amyloid plaques in the brain leads to deleterious downstream effects such as neurodegeneration and gliosis that ultimately cause behavioral deficits and memory loss. In recent years however, the exact role amyloid beta (A&beta) plays in AD has come into question. The most prevalent theory is that amyloid plaque deposition in the parenchyma is the main contributor of pathology in AD. More recent hypotheses state that A&beta deposition in the neural microvasculature in the form of cerebral amyloid angiopathy (CAA) plays a central role in AD. The present longitudinal study uses two transgenic mouse strains with distinctive genotypes, the 5XFAD and TgSwDI, to assess the relationship between location of A&beta deposition and resulting behavioral consequences at 3 and 6 months of age. Behavioral tests were used to assess aspects of spatial working memory as well as well as anxiety, activity level, motor coordination and limb strength. ELISA for A&beta was also performed to determine A&beta40 and A&beta42 soluble and insoluble levels. Finally, stereological quantification and area fraction analysis were done to look at vascular amyloid plaque deposition, total A&beta deposition, and activated microglia in different brain regions. At 3 months of age, the TgSwDI mouse was behaviorally impaired whereas the 5XFAD was not despite much higher levels of A&beta deposition in the parenchyma. At 6 months of age, both groups of transgenic animals had similar deficits. In this age group, A&beta deposition in the 5XFAD accumulated exponentially in the parenchyma while A&beta42 levels in the TgSwDI were only moderately elevated. These findings suggest that the location of A&beta deposition in the brain plays a major role in the development of downstream behavioral deficits seen in AD and therefore, is a factor that must be considered in the context of the Amyloid Cascade theory.