Apolipoprotein E is essential for amyloid deposition in the APP ^V717F transgenic mouse model of Alzheimer's disease

Abstract

We quantified the amount of amyloid ␤-peptide (A␤) immunoreactivity as well as amyloid deposits in a large cohort of transgenic mice overexpressing the V717F human amyloid precursor protein (APP V717F؉/؊ TG mice) with no, one, or two mouse apolipoprotein E (Apoe) alleles at various ages. Remarkably, no amyloid deposits were found in any brain region of APP V717F؉/؊ Apoe ؊/؊ TG mice as old as 22 mo of age, whereas age-matched APP V717F ؉/؊ Apoe ؉/؊ and Apoe ؉/؉ TG mice display abundant amyloid deposition. The amount of A␤ immunoreactivity in the hippocampus was also markedly reduced in an Apoe gene dose-dependent manner (Apoe ؉/؉ > Apoe ؉/؊ Ͼ Ͼ Apoe ؊/؊ ), and no A␤ immunoreactivity was detected in the cerebral cortex of APP V717F؉/؊ Apoe ؊/؊ TG mice at any of the time points examined. The absence of apolipoprotein E protein (apoE) dramatically reduced the amount of both A␤1-40 and A␤1-42 immunoreactive deposits as well as the resulting astrogliosis and microgliosis normally observed in APP V717F TG mice. ApoE immunoreactivity was detected in a subset of A␤ immunoreactive deposits and in virtually all thioflavine-Sfluorescent amyloid deposits. Because the absence of apoE alters neither the transcription or translation of the APP V717F transgene nor its processing to A␤ peptide(s), we postulate that apoE promotes both the deposition and fibrillization of A␤, ultimately affecting clearance of protease-resistant A␤/apoE aggregates. ApoE appears to play an essential role in amyloid deposition in brain, one of the neuropathological hallmarks of Alzheimer's disease.

A nontransgenic mouse model shows inducible amyloid-β (Aβ) peptide deposition and elucidates the role of apolipoprotein E in the amyloid cascade

“…The findings that apoE4 stimulates deposition of A␤ and apoE deficiency blocks formation of fibrillar A␤ deposits are in accordance with and extend previous studies with APP ϫ apoE doubletransgenic mice and with APP-transgenic mice on a null apoE mouse background (24,36,39,42,43). Formation of A␤ deposits did not require apoE, but it was accelerated significantly and in an isoform-specific fashion by apoE4 (Figs.…”

Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

“…Hepatic clearance of Ab1-40 is absent, 151 as is cerebral Ab deposition in apoE knockout animals. 152,153 Taken together, these findings suggest that apoE4 may contribute to AD pathology by its poor binding to Ab and thereby reducing its uptake and clearance from the cell. We have observed that Ab is cleared more efficiently from the periphery in E2 and E3 knock-in mice but not E4 mice (unpublished results) suggesting that Ab may be cleared in an isoformspecific manner.…”

Apolipoprotein E and Apolipoprotein E Receptors: Normal Biology and Roles in Alzheimer Disease

“…Whereas human data supports the idea that apoE isoforms result in differential susceptibilty to Ab aggregation in the brain, animal studies utilizing genetically modified mice that develop Ab deposition and express human apoE isoforms show more directly that human apoE isoforms have a strong effect on the time of onset of Ab aggregation as well as the amount, location, and conformation of Ab in the brain. Early studies with APP-transgenic (Tg) mice that develop Ab deposition in the brain (PDAPP and Tg2576 models) showed that when these mice were crossed with apoE 2/2 mice, there was less Ab deposition and a virtual abolishment of true amyloid plaques, plaque-associated neuritic dystrophy, CAA, and CAA-associated microhemorrhage in the absence of apoE (Bales et al 1997;Bales et al 1999;Holtzman et al 2000b;Fryer et al 2003). In addition, the anatomical pattern of Ab deposition differs in the absence of apoE (Holtzman et al 2000a;Irizarry et al 2000).…”