1 October 2010. What’s good for the heart may be good for the brain. Apolipoprotein A-I is the major component of high-density lipoprotein (HDL, or “good cholesterol”) in the blood, and is under intensive investigation by cardiovascular researchers for its ability to protect against heart disease. New evidence suggests that it might also help defend the brain against the cognitive deficits associated with Alzheimer’s-like pathology. In the September 16 issue of Journal of Biological Chemistry online, researchers led by Ling Li at the University of Alabama at Birmingham (now at the University of Minnesota in Minneapolis) report that overexpressing ApoA1 in a mouse model of AD protects the mice from cognitive deficits and curtails buildup of amyloid in brain blood vessels. Conversely, in an independent study published in the August 25 issue of Journal of Biological Chemistry online, researchers led by Radosveta Koldamova at the University of Pittsburgh in Pennsylvania found that AD mouse models that lack ApoA1 fare poorly on cognitive tests and deposit more Aβ in cerebral blood vessels than do AD mice with ApoA1. Together these papers add to the evidence that ApoA1 may help protect brain health, and suggest interventions that raise ApoA1 levels as potential future therapeutics for AD.
Previous research on the relationship between ApoA1 and AD has been inconsistent. Some studies have shown that low levels of ApoA1 are correlated with more severe AD, and high levels of ApoA1 with a lower risk of AD (see Merched et al., 2000; Saczynski et al., 2007; Bates et al., 2009). Other studies, however, have found no connection between ApoA1 and AD risk (see Song et al., 1997 and Reitz et al., 2004), or even a reverse association, with high HDL correlated with increased neurofibrillary tangles (see Launer et al., 2001 ). On the genetic front, one positive and one negative study have been published to date, see ApoA-1 gene overview on AlzGene.
Other studies have hinted at a cognitive effect. High HDL levels associate with sharper mental abilities in the elderly (see ARF related news story on Barzilai et al., 2006), while low HDL levels are a risk factor for memory decline in middle-aged adults (see Singh-Manoux et al., 2008). What might be behind these apparent benefits? ApoA1 is known to have anti-inflammatory effects, and indeed, in a mouse model of brain inflammation, an ApoA1 mimetic improved cognitive deficits (see Buga et al., 2006). ApoA1 has also been shown in-vitro to directly inhibit the aggregation of Aβ, suggesting it could lessen plaque formation (see Koldamova et al., 2001). Surprisingly, however, when researchers led by David Holtzman at Washington University in St. Louis, Missouri, crossed an AD mouse model with an ApoA1 null mouse, they saw no change in amyloid deposition in the brain (see Fagan et al., 2004).
To try to clarify the ApoA1 picture, first author Terry Lewis and colleagues from the University of Alabama group used an overexpression strategy, crossing AD mice transgenic for APP and PS1 mutations (APPswe/PSEN1ΔE9) with mice that expressed human ApoA1. The triple transgenic mice showed no difference in Aβ deposition in brain tissue compared to APP/PS1 mice, in agreement with the results of Holtzman and colleagues. However, in brain blood vessels the triple transgenics had about half the plaque load of the AD mice, suggesting that ApoA1 is protective. Lewis and colleagues also showed that the triple transgenics had less neuroinflammation, including less microglial and astrocyte activation. The most intriguing results were cognitive, however. At 10 months of age, the AD mice showed learning and memory defects in the Morris water maze, but the triple transgenics continued to perform as well as wild-type mice. The triple transgenics also performed better than the APP/PS1 mice in a memory retention test.
The results from this ApoA1 gain-of-function study dovetail with the loss-of-function findings from the University of Pittsburgh group. First author Iliya Lefterov crossed APP/PS1 mice to ApoA1 knockout mice, and likewise found that the triple transgenics showed no change in amyloid plaques in the brain tissue at 12 months of age, nor did they have differences in the levels of Aβ oligomers in the brain or in APP processing. However, compared to APP/PS1 mice, the brain blood vessels of the triple transgenics were far more clogged with amyloid plaque, showing a ten-fold increase in insoluble Aβ40 and a slight increase in Aβ42. Lefterov and colleagues also found cognitive defects in the mice lacking ApoA1, with triple transgenics performing worse on tests of spatial learning and memory retention than did APP/PS1 mice.
A strength of these papers, Holtzman said, is that even though the studies were performed independently and use different approaches, the results are consistent. He added that together the papers “indicate that HDL biology is important in aspects of Alzheimer’s pathology, and perhaps even in brain function.” Holtzman points out that the major component of brain HDL is ApoE, the strongest genetic risk factor for non-familial AD. Another brain HDL, ApoJ (also known as clusterin), ranks number 2 in the AlzGene Top Results. One difference between these cholesterols is that unlike ApoE and ApoJ, ApoA1 is not made in the brain; its concentration is much higher in blood, but enough ApoA1 crosses the blood-brain barrier to give it a presence in brain as well.
The next question, Holtzman suggested, is to find out how ApoA1 is improving memory. Is it protecting memory by preventing cerebral amyloid buildup, or can ApoA1 directly affect neurons and synapses in the brain?
Li and colleagues would like to know this too. To investigate whether the cholesterol can have a direct synaptic effect, Li said, they will compare the electrophysiology of slice cultures in the presence and absence of ApoA1. Another possibility, Li speculated, is that ApoA1 preserves memory by decreasing neuroinflammation. A third option is that amyloid deposits in cerebral blood vessels could harm brain function by decreasing the flow of nutrients into the brain, or by slowing Aβ clearance out of the brain, she said, adding that blood vessel amyloid burden also increases the risk of a cerebral hemorrhage.
Once they understand better how ApoA1 acts in the brain, Li said, the ultimate goal will be to move from animal studies to humans and see if the same relationship holds. Eventually, methods for raising ApoA1 could be evaluated in clinical trials to see if they protect against memory loss in AD. People can already increase their HDL, and therefore ApoA1, by exercise, a heart-healthy diet, and the vitamin niacin, Li said. In addition, new HDL-raising drugs may come out of the cardiovascular clinical research field.
Koldamova and colleagues are interested in analyzing their triple transgenic ApoA1 knockout mice at earlier ages. At 12 months, the AD mice are at the peak of Aβ deposition, which may be why the loss of ApoA1 produced no visible increase in accumulation, Koldamova said. She speculated that in younger mice, the researchers might see higher levels of Aβ oligomers in the brain tissue of the knockouts, either due to decreased clearance from brain, or due to the loss of ApoA1’s inhibitory effect on aggregation. They will also look for behavior and memory deficits at earlier ages, Koldamova said.
Yet another avenue will be to explore the role of ABCA1, the master regulator of cholesterol efflux from cells, Lefterov said. ABCA1 controls both ApoE and ApoA1, and knockouts of ABCA1 have been shown to increase amyloid deposition (see ARF related news story on Koldamova et al., 2005). “The connection between ApoE and ApoA1 might well be ABCA1, or even the master transcriptional regulator of all three guys, Liver X Receptor,” Lefterov said. He plans to examine transgenic mice that express human familial loss-of-function variants of ABCA1 for changes in ApoE and ApoA1.
Compared to its more famous cousins ApoE and ApoJ, ApoA1 has been largely overlooked till now in brain health, Koldamova said, but the new research suggests it might play an important role in AD and have therapeutic potential. “I hope [these results] will turn more attention on ApoA1.”—Madolyn Bowman Rogers.
Lewis TL, Cao D, Lu H, Mans RA, Su YR, Jungbauer L, Linton MF, Fazio S, Ladu MJ, Li L. Overexpression of human apolipoprotein A-I preserves cognitive function and attenuates neuroinflammation and cerebral amyloid angiopathy in a mouse model of Alzheimer’s disease. J Biol Chem. 2010 Sep 16. Abstract
Lefterov I, Fitz NF, Cronican AA, Fogg A, Lefterov P, Kodali R, Wetzel R, Koldamova R. Apolipoprotein A-I deficiency increases cerebral amyloid angiopathy and cognitive decifits in APP/PS1DeltaE9 mice. J Biol Chem. 2010 Aug 25. Abstract