Abstract # 2052 Serum amyloid A inhibits the clearance of amyloid beta from the brain

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia, and is thought to arise due to the abnormal accumulation of amyloid beta (Abeta) and tau in the brain. In the healthy brain, Abeta is predominantly cleared by transporters at the blood-brain barrier (BBB). Transporter deficiencies promote Abeta accumulation in the brain, which contributes to AD. Systemic inflammation is a risk factor for AD, and we have previously shown that lipopolysaccharide (LPS)-induced inflammation inhibits Abeta clearance from the brain (efflux). However, the contributing mechanisms of inflammation to Abeta efflux deficiency are not completely understood. Serum amyloid A (SAA) is an acute phase lipoprotein that is highly increased in blood following LPS treatment, and crosses the BBB. SAA has also been implicated in AD, but its mechanistic contributions are unclear. We hypothesized that SAA causes Abeta accumulation in the brain by inhibiting its efflux across the BBB. To test this, we assessed efflux of 125I-Abeta1-42 injected into the lateral ventricle of mice in the presence or absence of two isoforms of SAA-SAA1 and SAA2. We found that Abeta efflux was inhibited by SAA2, but not SAA1, suggesting an isoform-specific mechanism of Abeta efflux inhibition. Our findings suggest that SAA could be an important molecular link between systemic inflammation and AD.