New to the board--interesting article "Apoliporotein E antagonist . . ."

[sahara]

Just registered today so forgive me if this has been mentioned previously:

A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition
https://www.biologicalpsychiatryjournal ... X/fulltext

[sahara]

Try this link since the one above isn't working https://www.sciencedirect.com/science/a ... 231931323X

[BrianR]

This seems interesting (note, experiment done on transgenic mice).

For those who would like a slightly more accessible summary of this paywalled paper: https://www.sciencedaily.com/releases/2 ... 141409.htm

The publicly available part of the paper:

Background
The E4 isoform of apolipoprotein E (apoE4) is a major genetic risk factor for the development of sporadic Alzheimer’s disease (AD) and its modification has been an intense focus for treatment of AD in recent years.

Mehthods
We investigated the binding of apoE, a peptide corresponding to its low density lipoprotein receptor (LDRL) binding domain (aa 133-152, ApoEp) and modified ApoEp to amyloid precursor protein (APP) and their effects on Aβ production in cultured cells. Having discovered a peptide which blocks the interaction of apoE with N-terminal APP, we investigated the effects of this peptide and ApoEp on AD-like pathology and behavioral impairment in 3XTg and 5XFAD transgenic mice.

Results
ApoE and ApoEp, but not truncated apoE lacking the LDLR binding domain, physically interacted with N-terminal APP and thereby mediated Aβ production. Interestingly, the addition of six lysine residues to the N-terminal ApoEp (6KApoEp) directly inhibited apoE binding to N-terminal APP and markedly limited apoE- and ApoEp-mediated Aβ generation, presumably through decreasing APP cellular membrane trafficking and p44/42 mitogen-activated protein kinase phosphorylation. Moreover, while promoting apoE interaction with APP by ApoEp exacerbated Aβ and tau brain pathologies in 3XTg-AD mice, disrupting this interaction by 6KApoEp ameliorated cerebral Aβ and tau pathologies, neuronal apoptosis, synaptic loss, and hippocampal-dependent learning and memory impairment in 5XFAD mice without altering cholesterol, LDLR, and apoE expression levels.

Conclusions
These data suggest that disrupting apoE interaction with N-terminal APP may be a novel disease-modifying therapeutic strategy for AD.

[DebS]

Just registered today so forgive me if this has been mentioned previously:

A Novel Apolipoprotein E Antagonist Functionally Blocks Apolipoprotein E Interaction With N-terminal Amyloid Precursor Protein, Reduces β-Amyloid-Associated Pathology, and Improves Cognition
https://www.biologicalpsychiatryjournal ... X/fulltext

Hi and welcome, sahara!

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[Julie G]

So only six lysine residues stand between me and AD? FWIW, this is from Mark Mattson, who many of us are familiar with from his caloric restriction work. You can read a press release here that helps to translate the scientific jargon. This looks interesting!

[Fiver]

Hi sahara. Thanks.

A nice thought Julie!

Worth a try.

But what about apoe4's activity as a transcription factor or it's general toxicity? Just finished reading a paper showing the presence of E4 lowers the production of >50% of the proteins necessary for a functioning electron transport chain in mitochondria, including *all* of those necessary to built ATP synthase (Complex V). I assume all this would occur even if apoe4 no longer bound up AB in the spaces between cells.

.....hmmmm....sorry, I'm being a wet blanket, aren't I? Not enough coffee, I guess.

This is certainly worth trying, and may be a good one to eliminate some of the problems associated with E4.

...how's that for embracing the positive?

[BrianR]

... Just finished reading a paper showing the presence of E4 lowers the production of >50% of the proteins necessary for a functioning electron transport chain in mitochondria, including *all* of those necessary to built ATP synthase (Complex V). I assume all this would occur even if apoe4 no longer bound up AB in the spaces between cells. ...

I wonder about studies which indicate that APOE4 is just bad (rather than possibly bad in the context of modern diet/lifestyle) given that APOE4 was apparently evolutionarily conserved in humans/hominids for a million years or more. (And still widely present in the worldwide population.)

[Tincup]

But what about apoe4's activity as a transcription factor or it's general toxicity? Just finished reading a paper showing the presence of E4 lowers the production of >50% of the proteins necessary for a functioning electron transport chain in mitochondria, including *all* of those necessary to built ATP synthase (Complex V). I assume all this would occur even if apoe4 no longer bound up AB in the spaces between cells.

Issues with ApoE4 seem to show up mostly later in life. Wouldn't this be a life-long issue, if true?

[Julie G]

Issues with ApoE4 seem to show up mostly later in life. Wouldn't this be a life-long issue, if true?

Yeah, and also not all E4s are affected, even homozygotes. From my perspective that gives validity to Brians's theory.

I wonder about studies which indicate that APOE4 is just bad (rather than possibly bad in the context of modern diet/lifestyle) given that APOE4 was apparently evolutionarily conserved in humans/hominids for a million years or more. (And still widely present in the worldwide population.)

[Fiver]

Hi. I typed a reply earlier, but I guess I didn't hit the submit button....ugh. I spend a bit of time on that one.

Those a really good questions! Thanks everyone.

I went back to read some of the papers. They seems to show that the additional of apoe4 caused a variety of problems right away, while replacement with E3/E2 eliminated the problems quickly. The range of cellular problems that seem to show up are surprising - from changing the expression of 100s or 1000s of genes to compromising mitochondrial function to AB and tau aggregation. They are in cell cultures and mice, of course. And we know sometimes those things translate, sometimes they just don't. In some cases the researchers didn't do anything specific to stress them out or predispose them to AD. But, of course, the mice must have genes for human apoe4, then apoe3, added. So do the cells. Some of the studies use cell lines or strains of mice that are indeed predisposed to AD, which I guess makes sense from an experimental design standpoint. If none of the mice or cells even developed AD pathology, the researchers couldn't show that is goes away later.

So I agree that E4 pathology develops over time and accumulates as stress and age weaken the ability to renew and recover. There must be tipping points. And I agree that there's much we could do to slow the process (or speed it up).

But I just come away convinced that apoe4 has some impacts early. And that it is such a powerful factor it's worth addressing directly (like in this paper sahara shared).

Lately I've had some interactions with people who suggest that "AD is just what happens when people get old".

Some suggest that the potential benefits or E4 might somehow balance the costs in those at high risk (and, thus, clinical trials to replace E4 with E3 in patients are a bad idea). I guess it's possible. But I find myself resisting this view. Lots of awful diseases have some "upside", in certain environments, but we should still have treatments to offer. But I mostly just assume they've never experienced AD, and don't understand. Or maybe that's not fair and I'm not being 100% objective. That's hard to do sometimes.

Anyway, the more I read the more I think E4 is so influential that it's worth correcting or replacing it in some high risk individuals who wish to accept the risks of doing so, especially if it was during or after mid-life. So I get excited about papers like this one sahara shared.