Cerebral Microvascular Rather than Parenchymal Amyloid-β Protein Pathology Promotes Early Cognitive Impairment in Transgenic Mice

Abstract

Alzheimer’s disease (AD) is an age-dependent neurodegenerative condition that causes a progressive decline in cognitive function. Accumulation of amyloid β-protein (Aβ) in the brain is a prominent feature of AD and related disorders. The levels of Aβ accumulation alone are not a reliable predictor of cognitive deficits, which suggests other factors such as location of deposition may be more important. Aβ accumulates in AD brain in the form of parenchymal amyloid plaques and cerebral vascular deposits. Although both types of lesions can contribute to cognitive decline their temporal impact remains unclear. Moreover, cerebral microvascular pathology is identified as an early driver of cognitive impairment. Here for the first time, we compared two transgenic mouse strains, Tg-5xFAD and Tg-SwDI, which exhibit similar onset and anatomical accumulation of Aβ, but with distinct parenchymal and microvascular compartmental amyloid deposition, to assess the impact of their respective pathologies on cognitive impairment. Cohorts of each line were tested at 3 and 6 months of age to assess the relationship between spatial working memory and quantitative Aβ pathology. At 3 months of age, Tg-SwDI mice with onset of cerebral microvascular amyloid were behaviorally impaired, while the Tg-5xFAD, which had disproportionately higher levels of total Aβ, soluble oligomeric Aβ, and parenchymal amyloid were not. However, at 6 months of age, behavioral deficits for both groups of transgenic mice were evident, as the levels of Aβ pathologies in the Tg-5xFAD accumulated to extremely high amounts. The present findings suggest that early-onset cerebral microvascular amyloid deposition, that precedes high parenchymal levels of Aβ, may be an important early factor in the development of cognitive deficits. Key words: amyloid β protein; cerebral microvascular, parenchymal, pathology, cognitive impairment, transgenic mice

Early-onset Formation of Parenchymal Plaque Amyloid Abrogates Cerebral Microvascular Amyloid Accumulation in Transgenic Mice

“…1, A-C, all mice showed a progressive accumulation of soluble and insoluble A␤ species in the brain. At all ages, Tg-5xFAD mice accumulated higher levels of cerebral A␤ than Tg-SwDI mice, consistent with earlier studies (28). The bigenic Tg-SwDI/Tg-5xFAD mice generally accumulated much higher levels of A␤ than each single transgenic line.…”

“…Both of these approaches revealed that, at each of the ages examined, Tg-5xFAD mice possessed much higher levels of soluble A␤ oligomers compared with Tg-SwDI mice (Fig. 1, D-F), as reported previously (28). Although there tended to be higher levels of soluble A␤ oligomers in the bigenic Tg-SwDI/Tg-5xFAD mice compared with Tg-5xFAD mice, this was not significant.…”

“…Therefore, we next determined the levels of soluble A␤ oligomers in the different transgenic mouse lines using two complementary techniques. First, we used a sandwich ELISA technique to measure all forms of oligomers in the soluble brain fraction (28,46,47). Alternatively, we performed a quantitative dot blot analysis on soluble brain fractions using the A␤ oligomer-specific antibody OC11 (28,42,53).…”

“…First, we used a sandwich ELISA technique to measure all forms of oligomers in the soluble brain fraction (28,46,47). Alternatively, we performed a quantitative dot blot analysis on soluble brain fractions using the A␤ oligomer-specific antibody OC11 (28,42,53). Both of these approaches revealed that, at each of the ages examined, Tg-5xFAD mice possessed much higher levels of soluble A␤ oligomers compared with Tg-SwDI mice (Fig.…”

“…First, a sandwich ELISA was performed using m3D6 to capture A␤ species and biotinylated m3D6 for detection of oligomers of any size (28,46,47). Alternatively, soluble A␤ oligomers were analyzed by quantitative dot blot analysis using the polyclonal antioligomer antibody OC11, as described previously (28,42).…”