ApoE4 females, HF diet, endocannibinoids, hormones and squeaks all in one paper!

[circular]

In this thread we mention the need to get more familiar with AD researchers outside the US. Here's a May 2016 paper I don't think has been posted here out of Germany. The study was in mice but it looks fascinating. I've only read the abstract and discussion. If anyone can tell me what in the heck it is saying I'd appreciate it!

I came across this because I've been experimenting with Charlotte's Web cannabidiol oil for my EDS muscle spasms that I can't stretch out and which cause most of my pain. So far I seem to have a very low threshold that I can tolerate without it making my cognition getting a bit funky. It caused me to google 'apoe4 endocannibinoid' and this is what came up:

The Effect of a High-Fat Diet on Brain Plasticity, Inflammation and Cognition in Female ApoE4-Knockin and ApoE-Knockout Mice

Overall, our data hints at increased signs of neurodegeneration in ApoE4 mice and in ApoE-/- mice in comparison with WT mice. It appears that a HF diet reduces signs of neurodegeneration in ApoE4 mice and to a lesser extend in ApoE-/- mice, while it may increase signs of neurodegeneration in WT mice.

...

Overall, our data suggest that HF intake may induce a different effect in WT versus ApoE4 and ApoE-/- mice with respect to markers for neurodegeneration and cognition, possibly induced via cross-talk with ApoE isoforms and the endocannabinoid system, as proposed by Bartelt et al. [48]. We propose that HF intake might inhibit the compensatory mechanisms of neuroinflammation in aged female ApoE4 and ApoE-/- mice. Not only underlying mechanisms for neurogenesis, synaptic plasticity and neuroinflammation, but also the interaction between androgens, ApoE and HF dietary intake need to be elucidated in order to develop the dietary management for female APOE4-carriers.

Help This is so dense and out of my league but looks like it could be fascinating with a long tail!

[Asterling47]

I don't really understand this. Will follow the thread.

[circular]

Thanks for bringing this back up. I was surprised it garnered no apparent interest.

I've just reread the abstract and concluded it's horribly worded. The paper itself did seem dense as I recall, but the abstract doesn't have to be so confusing.

It refers to a citation where it's proposed the endocannabinoid system (ES), which in part influences the hormonal system, may interact differently with each of the ApoE forms (e.g. 2,3, and 4).

Then this paper suggests that the proposed connection between the ES and versions of ApoE may influence whether a high fat diet is neuroprotective or neurodegenerative, presumably through the resulting hormonal cascade, especially in females ... at least murine (mouse) ones.

While still theoretical, maybe this is worth following in the context of ongoing discussions over who should eat higher fat and who not? We often rely on biomarkers and how we feel to make these decisions. I wonder if the paper raises other flags we should be aware of.

That's the best I can do from my phone for now.

[SusanJ]

Interesting stuff. The paper (and some it cites) does suggest that high fat diet will only work for E4s and not others. I haven't been able to do a deep dive, but some of the references show the endocannibinoid system influences thermogenesis. And exposure to cold kicks the system into action so brown adipose tissue can burn white adipose tissue to stay warm. So there is likely an evolutionary reason for this system to help us stay warm in winter conditions.

In my short perusal, I haven't come to any conclusions whether CBD oil will help or hurt at this point.

It is worth reading their discussion, because they take a broad view of what might be affecting their results. From hormones, to diet to glucose transporters (no difference between types of mice). Did find this paragraph quite interesting.

ApoE is known for its anti-inflammatory effect. Addition of exogenous ApoE and its mimetics down-regulate activation of microglia and peripheral macrophages in vitro [46]. The absence of ApoE and also the ApoE4 isoform are therefore associated with secretion of inflammatory factors and increased neurinflammation [46]. ApoE4 enhances neuroinflammation either due to dysregulation of the nuclear factor-κB signaling cascade or due to an increase in cytokine levels [46,47]. The HF diet increases the number of microglia in WT mice exclusively. Strikingly, the ApoE-/- animals showed increased neuroinflammation when fed standard rodent chow, but a decrease when fed a HF diet. The same was found in ApoE4 mice.

(emphasis mine)

[circular]

Thanks Susan! This could leave 3/4s at a fork in the road. I think I recall that Julie said in mice a high fat diet is inflammatory but a carbohydrate diet isn't, whereas it's the opposite in people? (Needs confirmation.) If so it's even more intriguing that the effects of fat were antiinflammatory in apoe -/- and 4 mice.

[SusanJ]

This could leave 3/4s at a fork in the road.

Yep, a confusing fork for sure. Until there is more human research, I don't think we will know. Like you, I tend to go towards what feels like an improvement (pain, brain and other gains), along with a look at the labs to make sure I'm not fooling myself.

Going too low on the carbs, and I just don't feel well. Maybe that half-E3 effect.

Now back to histamine, lectins and that rabbit hole.

ps, have you ever used NAG?

[circular]

Thanks for mentioning the human studies. After walking away I was thinking I should come back and emphasize that part.

I can't take glucosamine because anything that makes normal people more flexible makes me too flexible and increases pain (EDS). I can't take fish oil for this reason as well, and even a serving of high omega fish makes my joints worse.