. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer disease. J Biol Chem. 2010 Nov 19;285(47):36958-68. Epub 2010 Sep 16 PubMed.


Please login to recommend the paper.


  1. These are an interesting set of papers, from two independent groups, that demonstrate the protective effect of ApoA-I against certain aspects of Aβ pathology in APP/PS1 transgenic mice. In the first paper by Lefterov et al. the authors took the approach of crossing APP/PS1 mice with ApoA-I KO mice and showed that this exacerbated the behavioral deficits of APP/PS1 mice. Most notably, the authors found that although the absence of ApoA-I had no effect on total brain Aβ levels, soluble Aβ oligomers, or parenchymal Aβ plaque load, there was a marked increase in cerebral amyloid angiopathy (CAA).

    The second paper by Lewis et al. took the opposite approach of breeding APP/PS1 mice with transgenic mice expressing human ApoA-I. There, studies found the opposite result where the triple transgenic mice had improved behavioral performance and decreased levels of CAA. Furthermore, this study went on to show that in the presence of ApoA-I there was a decrease in glial activation and pro-inflammatory cytokine production. Together, these studies further suggest that in addition to its well-known cardiovascular effects, ApoA-I may also have profound effects in the CNS that may be important in the pathogenesis of AD.

    On another point, I was particularly intrigued with how these two papers further support the concept studied in my lab, i.e. the relationship between CAA, neuroinflammation, and cognitive impairment. Earlier, we reported that cerebral microvascular amyloid deposition promotes neuroinflammation and behavioral deficits in the vasculotropic mutant APP mouse model Tg-SwDI (1,2). Reducing microvascular CAA in Tg-SwDI diminished the associated neuroinflammation, and this occurred in the absence of any changes in total Aβ load or the levels of soluble Aß oligomers (3).

    This earlier finding is consistent with the present results of Lefterov et al. that show in the absence of ApoA-I worsening behavioral performance in the APP/PS1 mice was associated with increased CAA load, not the level of soluble Aβ oligomers. Moreover, specifically reducing CAA-induced microglial activation improved behavioral performance in Tg-SwDI mice further strengthening the link between CAA, neuroinflammation, and cognitive impairment (4).

    These two papers indicate that ApoA-I fits as a protein that may be more specifically tailored towards the cerebral vascular contribution of AD and related disorders. First, Lefterov et al. show that ApoA-I hinders Aβ assembly into larger oligomeric/fibrillar structures and blocks their toxicity towards cultured human brain vascular smooth muscle cells. Proper assembly of Aβ is required for brain vascular smooth muscle cell toxicity (5,6). Second, ApoA-I may be intimately involved with efficient efflux of Aβ out of brain across the cerebral vasculature. Therefore, as the present two papers suggest, increasing or decreasing the expression of ApoA-I may have profound effects on the ability to clear Aβ at the level of cerebral blood vessel influencing the development of CAA. It would be interesting to determine what the plasma levels of Aβ are in these models with altered ApoA-I expression.

    Finally, the anti-inflammatory properties of ApoA-I may directly suppress localized CAA-induced neuroinflammation. In any case, these two manuscripts support further investigation into the specific contribution of CAA to neuroinflammation and cognitive impairment and how endogenous molecules, such as ApoA-I, may influence these processes.


    . Cerebral microvascular amyloid beta protein deposition induces vascular degeneration and neuroinflammation in transgenic mice expressing human vasculotropic mutant amyloid beta precursor protein. Am J Pathol. 2005 Aug;167(2):505-15. PubMed.

    . Early-onset subicular microvascular amyloid and neuroinflammation correlate with behavioral deficits in vasculotropic mutant amyloid beta-protein precursor transgenic mice. Neuroscience. 2007 Apr 25;146(1):98-107. Epub 2007 Feb 28 PubMed.

    . Reducing cerebral microvascular amyloid-beta protein deposition diminishes regional neuroinflammation in vasculotropic mutant amyloid precursor protein transgenic mice. J Neurosci. 2005 Jul 6;25(27):6271-7. PubMed.

    . Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. J Neurosci. 2007 Mar 21;27(12):3057-63. PubMed.

    . Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. J Neurochem. 1998 Jan;70(1):216-23. PubMed.

    . Disruption of pathologic amyloid beta-protein fibril assembly on the surface of cultured human cerebrovascular smooth muscle cells. Amyloid. 2001 Jul;8 Suppl 1:20-7. PubMed.

    View all comments by William Van Nostrand
  2. There is now substantial evidence that the accumulation of soluble and insoluble amyloid beta (Aβ) in the brain is a major factor in the etiology of AD. Preventing the accumulation of Aβ in the brain or facilitating its removal has become a major therapeutic goal for Alzheimer’s disease. Aβ-immunotherapy removes insoluble plaques of Aβ from the brain, but it appears that Aβ becomes entrapped in the perivascular drainage pathways by which a proportion of the Aβ is normally eliminated and results in increased severity of cerebral amyloid angiopathy (CAA). In addition, levels of soluble Aβ in the brain rise as a further indication that immunotherapy does not result in the complete elimination of Aβ from the brain. This has emphasized the importance of the perivascular drainage routes in the elimination of Aβ from the brain.

    The major impact of the experimental work published by Iliya Lefterov et al. is that it represents a step towards elucidating the role of major risk factors such as hypercholesterolemia and apolipoproteins in impeding the elimination of Aβ from the AD brain. Lipidated and non-lipidated ApoA-I inhibit the aggregation and toxicity of both Aβ 40 and 42. Deletion of the mouse ApoA-I gene significantly worsened cognitive performance in APP/PS1 transgenic mice, but did not change the total Aβ load. The important aspect is that arterial CAA was increased. The authors suggest that this may be due to the formation of Aβ fibrils in the vicinity of blood vessels and/or the effect that ApoA-I has on the smooth muscle cells. However, this does not explain the 5:1 ratio of Aβ40:42 observed in the APP/PS1ΔE9/ApoA-Iko mice. We suggest that ApoA-I may act as a chaperone, facilitating the transport of Aβ along the basement membranes of cerebral arteries. The absence of ApoA-I may result in a disruption to the normal dynamics of perivascular drainage, resulting in the accumulation of Aβ in the walls of arteries.

    The paper authored by Terry Lewis et al. describes high levels of HDL accompanied by unaltered levels of Aβ load, improved cognitive function and reduced neuroinflammation in the brains of APP/PS1 transgenic mice crossed with ApoA-I human replacement gene mice, compared to transgenic APP/PS1 mice. Overexpression of ApoA-I led to a reduction in CAA, although we do have concerns about using a non-specific dye (Congo red) as a sole marker for the amyloid deposition associated with blood vessels. These results suggest that ApoA-I facilitates the elimination of Aβ along the basement membranes of cerebral capillaries and arteries, but the overproduction of mutant Aβ in the extracellular spaces of the brain parenchyma leads to the formation of plaques and a rise in soluble Aβ.

    The roles that ApoA and ApoE may have in the dynamics of perivascular drainage and clearance of Aβ from the brain remain to be explored.

    View all comments by Roxana Carare

Make a Comment

To make a comment you must login or register.

This paper appears in the following:


  1. ApoA1: Does Good Cholesterol Protect the Brain?