Despite its spot on top of the pile of genetic risk factors for late onset Alzheimer disease, ApoE has remained an enigma on the pathophysiological level. Much study has been devoted to unraveling the interactions between ApoE and amyloid-β (Aβ), with results that were sometimes surprising, but always indicating a complex role for ApoE in Aβ homeostasis in the brain. Cutting through the complications, a report in Neuron last week brings a refreshingly simple take on the ApoE/Aβ relationship. Gary Landreth and colleagues at Case Western Reserve University in Cleveland, Ohio, present evidence that ApoE stimulates the degradation of soluble Aβ in the brain. This activity is isoform-dependent, with ApoE4 being the least effective at supporting Aβ degradation, a result that could explain why E4 is associated with up to a 25-times higher risk of AD than other alleles (see ARF related news story). In addition, the pro-proteolytic activity of ApoE depends on its lipidation status, a result that helps make sense of recent studies showing dramatically increased Aβ deposition in mice lacking ABCA1, the enzyme responsible for lipidating ApoE (see ARF related news story). The results also strengthen the idea that was floated several years ago (see ARF related news story) that liver X receptor agonists, which boost expression of both ApoE and ABCA1, have the potential to be developed as anti-amyloid therapies.
In a set of conceptually straightforward experiments, first author Qingguang Jiang and colleagues investigated the ability of brain microglia in culture to take up and degrade soluble Aβ42 peptide. After establishing that the intracellular protease neprilysin destroys Aβ42, they found that this destruction could be enhanced by adding ApoE to microglial cultures, or by inducing expression of ApoE and ABCA1 by treatment with a liver X receptor (LXR) agonist. The requirement for ApoE seems critical, since microglia from ApoE knockout mice showed a significant impairment in Aβ42 degradation, which was restored by adding exogenous ApoE to the cultures. None of the manipulations affected Aβ uptake, only degradation.
The degradation-enhancing activity of ApoE was dependent on the protein isoform, and on its lipidation status. In microglia from ApoE-/- mice, addition of any of the isoforms stimulated Aβ degradation, but ApoE2 was the most effective, while ApoE4 was the least. This tracks with the risk of AD in people carrying different ApoE alleles, where E2 confers the lowest risk, and E4 the highest. Adequate lipidation of ApoE mattered, too, as microglia from ABCA1 knockout mice displayed diminished Aβ degradation.
In addition to intracellular degradation pathways, microglia can effect degradation of extracellular Aβ by secreting insulin-degrading enzyme (IDE), an Aβ protease. However, astrocytes make and secrete the majority of ApoE in the brain, so the investigators wondered whether these cells, too, could secrete IDE. They found that in cultures of astrocytes, Aβ was indeed degraded extracellularly by IDE, and this activity depended on lipidated ApoE. Conditioned medium from ABCA1 knockout astrocytes was worse at degrading Aβ than conditioned medium from wild-type cells. In addition, lipidated ApoE stimulated Aβ breakdown by purified IDE.
All of the in vitro data point to a beneficial effect of ApoE on brain amyloid levels. To determine if this was the case in vivo, the authors treated one-year-old Tg2576 mice that express human amyloid precursor protein (APP) bearing the Swedish mutation with the LXR agonist GW3965. After four months of treatment, ApoE and ABCA1 protein levels had risen about twofold compared to untreated animals. While the treatment had no effect on APP levels or processing, the treated mice showed a 50 percent reduction in plaque number, a 67 percent reduction in plaque load, a 64 percent reduction in total Aβ and lower plaque-related inflammation in the hippocampus. The reduction in amyloid load was accompanied by improved memory performance in the contextual fear conditioning procedure.
“The present study documents a mechanism through which ApoE stimulates the degradation of soluble Aβ peptides within the brain,” the authors conclude. They favor a model where ApoE interacts with Aβ, and chaperones its proteolysis both inside microglia and in the extracellular space. They cannot, however, rule out other actions of ApoE, like changes in membrane lipid composition that might enhance intracellular proteolysis of Aβ. And how might the role of ApoE in Aβ clearance tie in with other functions of the protein that are potentially related to AD pathology, including its roles in neuronal survival, inflammation, and lipid trafficking in the brain? While these aspects of the ApoE/Aβ partnership remain to be clarified, the current data help explain recent findings that overexpressing ABCA1 in APP mice can prevent amyloid deposition (see ARF related news story) and provide additional support for the idea that boosting ApoE levels might be a good thing for the amyloid-beset brain.—Pat McCaffrey
- AD Genetics—Problems and Promise
- ABCA1 Loss Lowers ApoE, Not Amyloid; New ApoE Immunology
- ApoE Catalyst Conference Explores Drug Development Opportunities
- Paper Alert—ABCA1 Protects Against Amyloid Deposition
- Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008 Jun 12;58(5):681-93. PubMed.