| First Author | Lefterov I | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 47 | Pages | 36945-57 |
| PubMed ID | 20739292 | Mgi Jnum | J:166877 |
| Mgi Id | MGI:4849913 | Doi | 10.1074/jbc.M110.127738 |
| Citation | Lefterov I, et al. (2010) Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. J Biol Chem 285(47):36945-57 |
| abstractText | A hallmark of Alzheimer disease (AD) is the deposition of amyloid beta (Abeta) in brain parenchyma and cerebral blood vessels, accompanied by cognitive decline. Previously, we showed that human apolipoprotein A-I (apoA-I) decreases Abeta(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 Abeta(42) and decreases Abeta(42) toxicity in primary brain cells. To determine the effects of apoA-I on AD phenotype in vivo, we crossed APP/PS1DeltaE9 to apoA-I(KO) mice. Using a Morris water maze, we demonstrate that the deletion of mouse Apoa-I exacerbates memory deficits in APP/PS1DeltaE9 mice. Further characterization of APP/PS1DeltaE9/apoA-I(KO) mice showed that apoA-I deficiency did not affect amyloid precursor protein processing, soluble Abeta oligomer levels, Abeta plaque load, or levels of insoluble Abeta in brain parenchyma. To examine the effect of Apoa-I deletion on cerebral amyloid angiopathy, we measured insoluble Abeta isolated from cerebral blood vessels. Our data show that in APP/PS1DeltaE9/apoA-I(KO) mice, insoluble Abeta(40) is increased more than 10-fold, and Abeta(42) is increased 1.5-fold. The increased levels of deposited amyloid in the vessels of cortices and hippocampi of APP/PS1DeltaE9/apoA-I(KO) mice, measured by X-34 staining, confirmed the results. Finally, we demonstrate that lipidated and non-lipidated apoA-I significantly decreased Abeta toxicity against brain vascular smooth muscle cells. We conclude that lack of apoA-I aggravates the memory deficits in APP/PS1DeltaE9 mice in parallel to significantly increased cerebral amyloid angiopathy. |
