Apolipoprotein A-I Deficiency Increases Cerebral Amyloid Angiopathy and Cognitive Deficits in APP/PS1[delta]E9 Mice

A hallmark of Alzheimer disease (AD) is the deposition of amyloid beta (A beta ) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases A beta sub(40) aggregation and toxicity. Here we demonstrate that apoA-I in lipidated or non-lipidated form prevents the formation of high molecular weight aggregates of A beta sub(42) and decreases A beta sub(42) toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1[delta]E9 to apoA-I super(KO) mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1[delta]E9 mice. Further characterization of APP/PS1[delta]E9/apoA-I super(KO) mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble A beta oligomer levels, A beta plaque load, or levels of insoluble A beta in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble A beta isolated from cerebral blood vessels. Our data show that in APP/PS1[delta]E9/apoA-I super(KO) mice, insoluble A beta sub(40) is increased more than 10-fold, and A beta sub(42) is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1[delta]E9/apoA-I super(KO) mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased A beta toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1[delta]E9 mice in parallel to significantly increased cerebral amyloid angiopathy.