Htr-A1 - ApoE4 degrading enzyme

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
aphorist
Senior Contributor
Senior Contributor
Posts: 219
Joined: Sat Apr 19, 2014 3:47 am

Htr-A1 - ApoE4 degrading enzyme

Postby aphorist » Wed Aug 17, 2016 5:17 pm

HtrA1 is High-temperature requirement serine peptidase A1 (HtrA1) enzyme associated with ApoE in all isoforms.

Saghatelian and Chu (Salk Institute) also found that ApoE4—because it binds so well to HtrA1—keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells—and more of the breakdown products of the protein.

http://medicalxpress.com/news/2016-08-s ... -gene.html

ApropoE4
Contributor
Contributor
Posts: 363
Joined: Sun Feb 02, 2014 10:43 pm

Re: Htr-A1 - ApoE4 degrading enzyme

Postby ApropoE4 » Wed Aug 17, 2016 8:40 pm

I wonder what this means for functional medicine peeps who've previously claimed that apoe4 acts as a transcription factor, or that we should act to increase its levels.

User avatar
Julie G
Mod
Mod
Posts: 8680
Joined: Sat Oct 26, 2013 6:36 pm

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Julie G » Thu Aug 18, 2016 9:02 am

Thanks for sharing, aphorist. This new player seems to fit into Drs. Mahley’s theory nicely.

ApropoE4, I’ve never heard of a functional practitioner who recommends we try to raise APOE levels… although it seems an admirable goal given Rasmussen’s work:
Level of APOE in plasma, independent of genotype, is also a marker of risk, in this case, greater risk with lower levels.
"There was no evidence of interaction between APOE level and APOE genotype in predicting Alzheimer's disease," Katrine Rasmussen, MD, from the Department of Clinical Biochemistry at the Rigshospitalet of the University of Copenhagen, Denmark, reported. "It was the same in each [APOE] genotype."

Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919

Harrison
Senior Contributor
Senior Contributor
Posts: 278
Joined: Wed May 06, 2015 10:24 am

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Harrison » Thu Aug 18, 2016 10:37 am

Juliegee wrote:Level of APOE in plasma, independent of genotype, is also a marker of risk, in this case, greater risk with lower levels. "There was no evidence of interaction between APOE level and APOE genotype in predicting Alzheimer's disease," Katrine Rasmussen, MD, from the Department of Clinical Biochemistry at the Rigshospitalet of the University of Copenhagen, Denmark, reported. "It was the same in each [APOE] genotype."
Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919

Hi Julie,

I recently came across this commentary on the Rasmussen study from two very well-respected ApoE researchers:
http://www.ncbi.nlm.nih.gov/pubmed/25583643

I think the take home message is that the Rasmussen study is an interesting start, but they have concerns about the generalizability of it. Just thought it was worth mentioning.

User avatar
Stavia
Mod
Mod
Posts: 5265
Joined: Tue Apr 29, 2014 6:47 pm
Location: Middle Earth

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Stavia » Thu Aug 18, 2016 11:35 am

Harrison wrote:I think the take home message is that the Rasmussen study is an interesting start, but they have concerns about the generalizability of it. Just thought it was worth mentioning.


Harrison these are very wise words. And generalizable to many if not most studies. Team, it's the body of evidence that is meaningful.

User avatar
Julie G
Mod
Mod
Posts: 8680
Joined: Sat Oct 26, 2013 6:36 pm

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Julie G » Thu Aug 18, 2016 11:53 am

Thanks for sharing, Harrison- VERY interesting. I found the article behind a paywall, but will share relevant sections to the community via the Digital Media law fair use doctrine.

The authors make a good case against the relative short follow-up which may be very relevant for older participants (in terms of converting to AD,) but fairly useless for the 20 year olds who were followed for 4 years. I’d like to see the numbers re-analyzed only using a subset of older adults who are at greater risk for AD.
However, there are several concerns. Although the increased risk was still present after adjusting for the poten- tial confounds, these confounds, APOE genotype and age, both strongly affect plasma apoE levels. The age range of participants included in this study (20s–80s) with median follow-up of 4 years is both a strength and a weakness, and conversion to dementia may be difficult to assess in large populations over a (relatively) short median follow-up.

Less concerning, they discusses the separate pools of APOE in the periphery and CNS and how that may affect the interpretation of Rasmussen’s work. Even accounting for the relatively supposedly tiny interplay between the two pools, it remains significant that lower levels of APOE correlate with impaired cognition. I understand that this is a somewhat surprising and unexpected conclusion, but for that reason it certainly deserves further follow-up.
ApoE is synthesized peripherally primarily in the liver, and in the central nervous system (CNS) primarily by glia including astrocytes. The compartments are believed to be distinct, with little or no crosstalk across the blood–brain barrier.5,6 Even the type of lipoprotein particles found in the cerebro- spinal fluid (CSF) are different than the type of particles found in the blood. It is unknown whether or how the lower plasma apoE levels observed to be associated with increased risk of dementia relate to CNS levels. Smaller studies sug- gest that CNS levels are not different between AD and con- trol patients,7,8 and the Alzheimer’s Disease Neuroimaging Initiative data set shows the opposite effect—a relationship between elevated CSF apoE and cognitive decline.9

The authors also raise concerns with regards to the assay methods used which could certainly play a part in distorting results if found to be inaccurate, but the fact that the levels tracked very closely with APOE genotype (E2 exhibiting the highest levels & E4 the lowest) reveals at least a moderate level of precision.
Third, from a technical perspective, there may be concerns about enzyme-linked immunosorbent assay (ELISA) measurements in individuals of different genotypes, because Rasmussen et al show that their ELISA may not detect ApoE2, 3, and 4 protein levels equally well.1

Lastly, the authors ask excellent questions and conclude that further follow-up is warranted.
These concerns aside, taken at face value, the results from Rasmussen et al1 open a new set of fascinating questions about how peripheral ApoE levels are related to dementia. Plasma ApoE levels reflect both synthesis (peripherally, primarily in the liver) and clearance (again, peripherally, primarily in the liver). Is decreased synthesis or increased clearance reflective of underlying physiologi- cal properties that impact the CNS? Could peripheral apoE be part of the complex CNS–peripheral equilib- rium of Ab, with lower plasma apoE levels impacting to some extent CNS levels of Ab or other molecules of importance in CNS function? Or might peripheral apoE levels reflect broader issues related to inflammation, or to cholesterol metabolism, either of which may be relevant in mediating a biological process that impacts likelihood of dementia? Rasmussen et al1 provide an intriguing data set that motivates further exploration of these questions.

alangreenmd
Contributor
Contributor
Posts: 62
Joined: Mon Jan 15, 2018 3:32 pm

Re: Htr-A1 - ApoE4 degrading enzyme

Postby alangreenmd » Mon Feb 05, 2018 11:49 pm

High APOE in CSF associated with AD reflects leaky BBB.
Low APOE in plasma probably reflects low synthesis by astroctes.
Problem with APOE4 is lack function. Therefore if in old age E3 synthesize less will cause less function. In mouse studies APOE null mice same as APOE4 mice.
Decrease APO3 in old age good explanation some risk AD in non-E4 in old age.

Orangeblossom
Senior Contributor
Senior Contributor
Posts: 802
Joined: Tue Nov 07, 2017 10:11 am

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Orangeblossom » Tue Feb 06, 2018 12:44 am

aphorist wrote:HtrA1 is High-temperature requirement serine peptidase A1 (HtrA1) enzyme associated with ApoE in all isoforms.

Saghatelian and Chu (Salk Institute) also found that ApoE4—because it binds so well to HtrA1—keeps the enzyme from breaking down the tau protein, responsible for tau tangles associated with Alzheimer's.

When they compared how HtrA1 degraded ApoE4 with ApoE3, they found that the enzyme processed more ApoE4 than ApoE3, chewing ApoE4 into smaller, less stable fragments. The researchers confirmed the observation in both isolated proteins and human cells. The finding suggests that people with ApoE4 could have less ApoE overall in their brain cells—and more of the breakdown products of the protein.

http://medicalxpress.com/news/2016-08-s ... -gene.html



Yes, that would tie on with other things I have seen about lower levels of APOE with E4..E4s generally have less overall APOE compared to E2 or E3

It also brings to mind that ABCA1 polymorphisms can be related to levels of APOE and also linked to dementia risk. (involved in lipidating APOE in the brain) https://academic.oup.com/cardiovascres/ ... 05/2931058

and here:

"ApoE, like apoA-I, interacts with ABCA1 to generate nascent HDL particles (14). The C-terminal hydrophobic domain of apoE (residues 222–299) is necessary for its stimulation of ABCA1-dependent cholesterol efflux, so that apoE isoforms interact equivalently. Nascent apoE-HDL particles may also arise following the endocytosis of VLDL by hepatocytes with apoE being retained in early endosomes and recycled to the cell surface (15). ApoE may move between HDL and postprandial triglyceride-rich particles, probably as a lipid complex. As a consequence, apoE on HDL declines at the height of lipid absorption. While nascent apoE-HDL is produced primarily by hepatocytes or macrophages, the steady-state distribution of apoE among lipoprotein classes is equivalent regardless of the tissue source (7).

ApoE is found on minor HDL subclasses, including particles in which it is the sole apoprotein and particles that also contain apoA-I. In general, HDL particles containing apoE are larger than apoA-I-containing HDL particles. This may be related to differences in the nature of the amphipathic α-helices impacting on their association with phospholipid so that apoE is better able to accommodate LCAT-mediated core expansion of the HDL (16, 17). With low levels of hepatic lipase or high peripheral cholesterol load, apoE-rich HDL accumulates in the plasma. The apoE gene is a target of LXRα in nonhepatic tissues. When LXR is activated, enlarged HDL is generated but only in the presence of apoE and this is abrogated by CETP (18). Hence the HDL accumulating with CETP inhibition or inactive mutants is generally enriched in apoE."

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2674757/

From the article: "The results need be tested and confirmed in animal studies before researchers can be sure that HtrA1 is the link between ApoE4 and Alzheimer's in humans. But if they hold true, they could point toward a better understanding of the disease and potential new treatment strategies" Well I suppose that is a thought. Maybe they can do something about it.
Last edited by Orangeblossom on Tue Feb 06, 2018 6:07 am, edited 3 times in total.

Orangeblossom
Senior Contributor
Senior Contributor
Posts: 802
Joined: Tue Nov 07, 2017 10:11 am

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Orangeblossom » Tue Feb 06, 2018 12:57 am

ApropoE4 wrote:I wonder what this means for functional medicine peeps who've previously claimed that apoe4 acts as a transcription factor, or that we should act to increase its levels.



Yes it does make you think, doesn't it. I am unsure about the evidence for it being a transcription factor and still not convinced about that. But not done much reading on that yet. If anyone has any good links or research on it would be interested to read.

Ah, sorry, found it here https://www.medicalnewstoday.com/articles/319131.php?sr

The full paper is here. http://www.jneurosci.org/content/36/3/685

It is a bit confusing though as seems to show APOE4 suppressing genes rather than promoting them:
Last edited by Orangeblossom on Tue Feb 06, 2018 8:29 am, edited 2 times in total.

Orangeblossom
Senior Contributor
Senior Contributor
Posts: 802
Joined: Tue Nov 07, 2017 10:11 am

Re: Htr-A1 - ApoE4 degrading enzyme

Postby Orangeblossom » Tue Feb 06, 2018 2:20 am

Julie G wrote:Thanks for sharing, aphorist. This new player seems to fit into Drs. Mahley’s theory nicely.

ApropoE4, I’ve never heard of a functional practitioner who recommends we try to raise APOE levels… although it seems an admirable goal given Rasmussen’s work:
Level of APOE in plasma, independent of genotype, is also a marker of risk, in this case, greater risk with lower levels.
"There was no evidence of interaction between APOE level and APOE genotype in predicting Alzheimer's disease," Katrine Rasmussen, MD, from the Department of Clinical Biochemistry at the Rigshospitalet of the University of Copenhagen, Denmark, reported. "It was the same in each [APOE] genotype."

Plasma levels of apolipoprotein E and risk of dementia in the general population.
http://www.ncbi.nlm.nih.gov/pubmed/25469919


In this abstract it also states:

"In a subanalysis, the -219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype"

That is of interest, I was never sure whether that promoter was a good or a bad thing. I was unsure if it was good (mine is GG) as increased both E4 and E3. But maybe that is not the important thing, just promoting it seems to be good. But then I'm sure there are plenty of other papers say the opposite! It never seems to be conclusive does it. I will hold on to the positives for now, so glad to see this.


Return to “Science and Research”

Who is online

Users browsing this forum: No registered users and 13 guests