36 replies to this topic

[theblob]

WELL, only explanation maybe: the doubt might not be on bexarotene, but on the implications of amyloid beta plaques...

[ymc]

Unfortunately, even if it works, it only helps non-APOE Alzheimer disease. This is because its mechanism is to stimulate expression of APOE. But if your APOE is broken, which is the case for majority of Alzheimer patients, then overexpression of a broken gene still gives you broken protein.

[niner]

Unfortunately, even if it works, it only helps non-APOE Alzheimer disease. This is because its mechanism is to stimulate expression of APOE. But if your APOE is broken, which is the case for majority of Alzheimer patients, then overexpression of a broken gene still gives you broken protein.

Do we know that's the case? Assuming that the mechanism in Alzheimers is strictly based on ApoE, what if ApoE4 still had some activity in plaque clearance? Or maybe the problem with the e4 form is that it isn't expressed as well? I think it's worth looking at. There's a clinical trial with it, so they'll surely know the ApoE genotype of the patients. (at least I hope they will...) I think the failure of complete replication is not the end of the world, because the other groups saw clearance of soluble amyloid protein and at least one group saw a cognitive improvement.

[ymc]

Unfortunately, even if it works, it only helps non-APOE Alzheimer disease. This is because its mechanism is to stimulate expression of APOE. But if your APOE is broken, which is the case for majority of Alzheimer patients, then overexpression of a broken gene still gives you broken protein.

Do we know that's the case? Assuming that the mechanism in Alzheimers is strictly based on ApoE, what if ApoE4 still had some activity in plaque clearance? Or maybe the problem with the e4 form is that it isn't expressed as well? I think it's worth looking at. There's a clinical trial with it, so they'll surely know the ApoE genotype of the patients. (at least I hope they will...) I think the failure of complete replication is not the end of the world, because the other groups saw clearance of soluble amyloid protein and at least one group saw a cognitive improvement.

http://www.ncbi.nlm....pubmed/10359567

I think you are right that APOE E4 is not entirely nonfunctional. Therefore it is possible that if you stimulate its expression to a certain level, it might help. But of course, trials are needed to confirm whether this theory works or not.

[tunt01]

New Bexarotene study seems pretty interesting.  It has characterized the mechanism of action in how bexarotene alters AD pathology -- by increase lipidation of APOE4 to make it more like APOE3.  The study seems to indicate that bexarotene increases the quality of APOE, not the quantity.  This could be a very big deal.

 

 

Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is less lipidated than its corresponding AD-benign form, apoE3, and it has been suggested that the pathological effects of apoE4 are mediated by lipid-related mechanisms. ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1, respectively) are the most important apoE-lipidating proteins. The expression of these proteins, as well as that of apoE, is controlled by the transcription regulation retinoid X receptor (RXR)-liver X receptor (LXR) system. In the present study, we investigated the effects of the RXR agonist bexarotene on mRNA and protein levels of apoE, ABCA1, and ABCG1 in young, naive apoE3- and apoE4-targeted replacement mice and assessed the extent to which this reverses the apoE4-driven pathological phenotype. This investigation reveled that bexarotene increases the mRNA and protein levels of ABCA1 and ABCG1 in hippocampal neurons, but has no effect on the corresponding levels of apoE. These findings were associated with reversal of the lipidation deficiency of apoE4 and of the cognitive impairments of apoE4 mice in several tests. Furthermore, bexarotene reversed the apoE4-driven accumulation of Aβ42 and hyperphosphorylated tau in hippocampal neurons, as well as the apoE4-induced reduction in the levels of the presynaptic marker vesicular glutamatergic transporter 1 (VGluT1). In conclusion, the results show that treatment of apoE4 mice with the RXR agonist bexarotene reverses the apoE4-induced cognitive and neuronal impairments in vivo and suggest that this is due to reversal of the lipidation deficiency of apoE4. This puts forward the possibility that RXR activation and increased levels of ABCA1 and ABCG1 could be useful in the treatment of human apoE4 carriers.

 

Further discussed and commented by researchers here:  http://www.alzforum....rapeutic-target

 

reposted - because the other thread seems dead and most are participating here.

 

Edited by prophets, 26 May 2014 - 07:57 PM.

[tunt01]

Dr. Koldamova explains how induction of ABCA1 Transporter prevents ABeta oligmers and ALZ pathology.

 

 

 

ABCA1 is regulated by RXR and LXR.  Interesting RXR agonists lower triglycerides and raise HDL, consistent with Koldamova's remarks that ABCA1 is driving the mechanism of action.  APOE4 allele individuals often have higher trigs and lower HDL, which seems to be partially reversed via RXR activation.  Based on Koldamova's work, levels of HDL could be considered an indication of the level of intrinsic ABCA1 functionality.

 

Telmisartan also activates ABCA1 via PPAR-gamma, which (I believe) is an alternative pathway (from RXR) to directly induce ABCA1.  It explains why Telmisartan reduces amyloid burden and is AD preventative.

Edited by prophets, 22 June 2014 - 02:55 PM.

[tunt01]

Over the years we have seen curcumin emerge as a top supplement for the treatment of Alzheimer's.  Given the ABCA1 Transporter hypothesis that explains Bexarotene's ability to reverse ALZ pathology, how does curcumin fit in the equation?  According to one paper, it may have similar mediating properties:

 

Curcumin induces ABCA1 expression and apolipoprotein A-I-mediated cholesterol transmembrane in the chronic cerebral hypoperfusion aging rats

Cerebral hypoperfusion or aging often results in the disturbances of cholesterol and lipoprotein, which have been well depicted as a common pathological status contributing to neurodegenerative diseases such as vascular dementia (VaD) and Alzheimer's dementia (AD). The pathway of the liver X receptor-β (LXR-β)/retinoic X receptor-α (RXR-α)/ABCA1 plays a vital role in lipoprotein metabolism. Curcumin, a kind of phenolic compound, has been widely used. It has been reported that curcumin can reduce the levels of cholesterol in serum, but the underlying mechanisms are poorly understood. In this study, we evaluated the effects of curcumin on the cholesterol level in brain, vascular cognitive impairment and explored whether the mechanisms for those effects are through activating LXR-β/RXR-α and ABCA1 expression and apoA-I. With a Morris water test, we found that curcumin treatment could attenuate cognitive impairment. With HE and Nissl staining, we found that curcumin could significantly ameliorate the abnormal changes of pyramidal neurons. Meanwhile, the expression of LXR-β, RXR-α, ABCA1 and apoA-I mRNA and protein were increased in a dose-dependent manner after curcumin treatment. Interestingly, both serum HDL cholesterol and total cholesterol levels were statistically higher in the curcumin treatment group than those other groups. We conclude that curcumin has the ability to activate permissive LXR-β/RXR-α signaling and thereby modulate ABCA1 and apoA-I-mediated cholesterol transmembrane transportation, which is a new preventive and therapeutic strategy for cerevascular diseases.

 

 

 

Edited by prophets, 25 June 2014 - 07:31 PM.