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Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE. ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models. Science. 2012 Mar 23;335(6075):1503-6. Epub 2012 Feb 9 PubMed.
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University of Illinois
The issue of whether to increase or decrease ApoE levels for AD therapy is confounded by the multiple functions of ApoE. In a landmark paper, Landreth and coworkers clearly demonstrate that bexarotene treatment, an RXR agonist, increases endogenous mouse ApoE levels, enhancing soluble Aβ clearance within hours, in APP/Aβ transgenic mice. Further, in this significant paper, bexarotene rapidly reduced Aβ plaque burden by greater than 50 percent in 72 hours and reversed cognitive deficits, and thus represents a novel AD therapy. These data are in apparent contrast with studies in which Aβ deposition is greatest with mouse-ApoE compared to the lack of ApoE (ApoE-/-) in multiple APP/Aβ transgenic models (e.g., publications from Fagan/Holtzman and Bales/Paul). However, these same studies further demonstrate that amyloid burden from greatest to least is: mouse-ApoE, ApoE-/-, ApoE4. Thus, one perspective on this issue of whether a therapeutic approach should increase or decrease ApoE is to compare ApoE4 to ApoE-/-. While ApoE4 has a beneficial effect on Aβ deposition compared to ApoE-/-, ApoE4 has a negative effect on LTP and Aβ-induced neurotoxicity. Indeed, the magnitude of LTP in both the absence (1) and presence (2) of oligomeric Aβ is greater with ApoE-/- mice compared to ApoE4 targeted replacement mice ex vivo. Furthermore, neuronal survival after oligomeric Aβ treatment is greatest in neurons co-cultured with glia isolated from ApoE-/- mice compared to neurons with glia from ApoE4 targeted replacement mice (3). Thus, although raising ApoE levels may exert a beneficial function on Aβ deposition, ApoE4 may also represent a toxic gain of function. Therapeutics that target specific aspects of ApoE function, of which bexarotene should be considered, may prove to be the most beneficial approach for AD.
References:
Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Ye GL, Sotak M, Sullivan PM, Pasternak JF, LaDu MJ. ApoE isoform affects LTP in human targeted replacement mice. Neuroreport. 2004 Dec 3;15(17):2655-8. PubMed.
Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Stine WB, Manelli A, Sullivan P, Pasternak JF, LaDu MJ. ApoE isoform-specific effects on LTP: blockade by oligomeric amyloid-beta1-42. Neurobiol Dis. 2005 Feb;18(1):75-82. PubMed.
Manelli AM, Bulfinch LC, Sullivan PM, LaDu MJ. Abeta42 neurotoxicity in primary co-cultures: effect of apoE isoform and Abeta conformation. Neurobiol Aging. 2007 Aug;28(8):1139-47. PubMed.
View all comments by Leon TaiMichigan State University
The data presented in this paper show the most rapid removal of Aβ of any systemically applied therapy. They hold great promise for testing the amyloid hypothesis, and possibly for application in secondary prevention trials of asymptomatic patients where anti-amyloid therapies are most likely to be effective. However, reasonable dosages need to be identified before large-scale human applications can be considered. The extreme doses used in cancer studies did indicate some severe reactions to the agent, albeit rare. Our center (Byrd Alzheimer Institute) will not be writing prescriptions at this time, but look forward to well-controlled clinical trial opportunities.
Some LXR ligands interact directly with γ-secretase. The structure of bexarotene suggests that it, too, may have a direct interaction with the complex. Given the rapidity of the effects observed, it would be interesting to see data for this compound in a cell-free γ-secretase assay.
Whilst bexarotene is indeed FDA approved for oncology, the safety profile is unlikely to translate to chronic administration in an elderly population—particularly not at equivalent doses to those used. This would indicate that more potent/bio-available analogues will be required. Understanding the exact properties of the drug with regard to amyloid reduction will be critical.
References:
Czech C, Burns MP, Vardanian L, Augustin A, Jacobsen H, Baumann K, Rebeck GW. Cholesterol independent effect of LXR agonist TO-901317 on gamma-secretase. J Neurochem. 2007 May;101(4):929-36. PubMed.
View all comments by Adam KlineUSC Alzheimer’s Therapeutic Research Institute
I think this is a very intriguing paper. Most therapeutic programs have targeted amyloid peptide production, or immune-mediated clearance of Aβ. This novel strategy targets ApoE-mediated clearance of Aβ through activation of the retinoid X receptors. Since ApoE is by far the strongest genetic risk factor in sporadic AD, it is reasonable to assume that ApoE-related therapeutics may be disease modifying. That idea is backed by strong experimental data from studies in animal models. And since bexarotene is already FDA approved for another indication, it may advance rapidly into human studies.
So this is very exciting work indeed. However, mouse models have not reliably predicted therapeutic effects in humans. Caution is crucial until human studies confirm target engagement (enhanced amyloid peptide clearance). Trials have already shown that two monoclonal antibodies reduce brain amyloid load as seen by PET imaging, so those agents may be more likely to succeed. However, the activity of bexarotene should be straightforward to confirm by looking for changes in the cerebrospinal fluid ApoE and Aβ. If the mouse pharmacodynamic effect is confirmed, bexarotene could be an excellent candidate for studies in prodromal and preclinical AD.
Harvard Medical School
This is very exciting work. With the RXR agonist bexarotene, a drug approved by the FDA, three different AD mouse models clear amyloid-β and regain cognitive function. It is amazing that it works so fast and dramatically. However, none of these models has tau pathology. How does it affect tau pathology? Before, we also had some good candidates that reduced Aβ plaque and rescued cognitive impairment in animal models, but in clinical trials, they failed. So we look forward to the next clinical trial with bexarotene.
Also, ApoE4 increases the risk of developing the late-onset form of AD, and a lot of studies have shown that ApoE4 is toxic and that more ApoE4 leads to more plaques. If bexarotene enhances the expression of ApoE, then AD patients with E4 alleles will have more toxic ApoE4. I wonder if bexarotene will be beneficial to those patients. It has also been reported that ApoE protein level decreases on bexarotene. If so, then bexarotene may be of benefit. The effect of bexarotene probably depends on which is more important, the decrease of ApoE or the toxicity of ApoE4.
Retired
Before we break out the champagne, let us be aware that mouse ApoE and human ApoE are not the same!
References:
Maloney B, Ge YW, Alley GM, Lahiri DK. Important differences between human and mouse APOE gene promoters: limitation of mouse APOE model in studying Alzheimer's disease. J Neurochem. 2007 Nov;103(3):1237-57. PubMed.
The report by Cramer et al. is potentially exciting because it offers a plausible explanation as to why ApoE4 should be a risk factor for AD, and more importantly suggests that bexarotene, an off-the-shelf retinoid X receptor agonist, may prove to be an effective treatment for the disease. Unfortunately, our results with bexarotene treatment in the APPSwFILon, PSEN1*M146L*L286V (5XFAD) mouse model of Alzheimer's disease failed to provide positive results. This 5XFAD model is one of the most aggressive of all AD models, with Aβ deposits appearing as early as eight weeks after birth. It may be that the high rate of Aβ deposition in this model overwhelms the ability of bexarotene to stimulate clearance. However, it does indicate that testing should be done in other AD transgenic models to gain a fuller picture of what is taking place.
We started to feed the 5XFAD mice at seven to eight weeks of age with chow containing 500 mg/kg bexarotene, which corresponds to a consumption of 2 mg per day or an oral dose of 100 mg/kg/day (n = 8). Control 5XFAD mice were fed normal chow (n = 7). Mice were sacrificed at 21, 31, and 50 days after feeding commenced. We found no difference between test and control mice in a standard Morris water maze test, and no significant difference in the number of Aβ deposits.
Transgenic mouse models of Alzheimer's disease vary widely in their properties. The model we studied may be an unsatisfactory representation of AD pathology. However, the results do illustrate that the phenomenon described by Cramer et al. is not entirely straightforward. More in-depth investigation is clearly indicated.
View all comments by Pat McGeerIndiana University School of Medicine
Reply to comment by Jian-Ping Guo, P.L. McGeer, and Claudia Schwab
We communicated the results of our study in advance of publication with these authors.
It is important that oral administration of bexarotene employ the micronized form of the drug (Targretin™, Eisai, Inc.) due to the efficiency of absorption in the gut. The FDA filing documents a sixfold difference in efficacy compared to the powdered form of bexarotene.
Dr. Guo et al. note that their model might be too robust to observe an effect of bexarotene. We tested the effect of bexarotene in a similarly aggressive model of AD, the APP/PS1-21 mice. A 20-day treatment resulted in a reduction of soluble Aβ and an approximately 35 percent decrease in plaque number. Importantly, we found improved behavior in both the Morris water maze and contextual fear conditioning. Thus, I don't think that this consideration explains their results.
The correspondents noted that they did not find a change in plaque load in drug-treated mice. Indeed, we observed this, too. One of the surprising findings was that chronic drug treatment of APP/PS1 mice was associated with an immediate fall in plaque burden, which then returned to the levels observed in vehicle-treated mice. We found improved behavior in the same two behavioral assays after 90 days of treatment. One possible conclusion from this experiment is that plaques don't matter, and we are actively pursuing this issue.
It should also be noted that in the periphery, there is robust induction of P450 enzymes with sustained bexarotene administration. It is possible that the dose of drug required to maintain microglia in an "alternatively activated" (M2) state, which is anti-inflammatory and conducive to plaque phagocytosis, is greater than that necessary to drive ApoE/HDL induction. The sustained drug treatment may result in efficient drug degradation, lowering the CNS and plasma levels of bexarotene. We are now testing this possibility.
We couldn't agree more that further in-depth study is necessary, and are anxious to have our studies repeated in others' hands.
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