RGD Reference Report - Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice. - Rat Genome Database
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Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive deficits in APP/PS1DeltaE9 mice.

Authors: Lefterov, I  Fitz, NF  Cronican, AA  Fogg, A  Lefterov, P  Kodali, R  Wetzel, R  Koldamova, R 
Citation: Lefterov I, etal., J Biol Chem. 2010 Nov 19;285(47):36945-57. Epub 2010 Aug 25.
RGD ID: 5508213
Pubmed: (View Article at PubMed) PMID:20739292
DOI: Full-text: DOI:10.1074/jbc.M110.127738

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.

Annotation

Disease Annotations    

Objects Annotated

Genes (Rattus norvegicus)
Apoa1  (apolipoprotein A1)

Genes (Mus musculus)
Apoa1  (apolipoprotein A-I)

Genes (Homo sapiens)
APOA1  (apolipoprotein A1)


Additional Information