Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Insights and discussion from the cutting edge with reference to journal articles and other research papers.
Post Reply
User avatar
TheBrain
Contributor
Contributor
Posts: 1413
Joined: Fri Oct 03, 2014 12:12 pm

Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by TheBrain »

https://www.ncbi.nlm.nih.gov/pubmed/31383855

Abstract
Alzheimer's disease (AD) is the most common dementia in the elderly. Treatment for AD is still a difficult task in clinic. AD is associated with abnormal gut microbiota. However, little is known about the role of fecal microbiota transplantation (FMT) in AD. Here, we evaluated the efficacy of FMT for the treatment of AD. We used an APPswe/PS1dE9 transgenic (Tg) mouse model. Cognitive deficits, brain deposits of amyloid-β (Aβ) and phosphorylation of tau, synaptic plasticity as well as neuroinflammation were assessed. Gut microbiota and its metabolites short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and 1H nuclear magnetic resonance (NMR). Our results showed that FMT treatment could improve cognitive deficits and reduce the brain deposition of amyloid-β (Aβ) in APPswe/PS1dE9 transgenic (Tg) mice. These improvements were accompanied by decreased phosphorylation of tau protein and the levels of Aβ40 and Aβ42. We observed an increases in synaptic plasticity in the Tg mice, showing that postsynaptic density protein 95 (PSD-95) and synapsin I expression were increased after FMT. We also observed the decrease of COX-2 and CD11b levels in Tg mice after FMT. We also found that FMT treatment reversed the changes of gut microbiota and SCFAs. Thus, FMT may be a potential therapeutic strategy for AD.
ApoE 4/4 - When I was in 7th grade, my fellow students in history class called me "The Brain" because I had such a memory for detail. I excelled at memorization and aced tests. This childhood memory helps me cope!
rws
Contributor
Contributor
Posts: 43
Joined: Wed Aug 23, 2017 2:04 am

Re: Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by rws »

In case you are wondering:
B6C3-Tg(APPswe,PSEN1dE9)85Dbo/Mmjax
Also Known As: APP/PS1

APP/PS1 are double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9), both directed to CNS neurons. Both mutations are associated with early-onset Alzheimer's disease. These mice may be useful in studying neurological disorders of the brain, specifically Alzheimer's disease, amyloid plaque formation and aging.
https://www.jax.org/strain/004462
FamilyHistory
New User
New User
Posts: 2
Joined: Sun Jun 11, 2023 12:38 pm

Re: Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by FamilyHistory »

Since Alzheimer's has also causal factors in the gut microbiome, this promising fecal implant for Parkinson's symptomatic improvement, https://www.thelancet.com/journals/ecli ... 1/fulltext, and the reverse (fecal implant from humans with Alzheimer's causes cognitive decline and biomarkers in rats https://academic.oup.com/brain/article/ ... ogin=false ), this approach gives me possible hope for fecal implant treatment to improve hippocampal neurogenesis...... These mouse studies in this post also seem promising.

Could somewhat simple one-time fecal transplant prevent decline in those with 1 or 2 copies of Apoe4? Thoughts or new findings???
User avatar
floramaria
Support Team
Support Team
Posts: 1450
Joined: Tue Jul 04, 2017 11:22 am
Location: Northern New Mexico

Re: Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by floramaria »

FamilyHistory wrote: Sat Jun 08, 2024 5:14 pm Since Alzheimer's has also causal factors in the gut microbiome, this promising fecal implant for Parkinson's symptomatic improvement, https://www.thelancet.com/journals/ecli ... 1/fulltext, and the reverse (fecal implant from humans with Alzheimer's causes cognitive decline and biomarkers in rats https://academic.oup.com/brain/article/ ... ogin=false ), this approach gives me possible hope for fecal implant treatment to improve hippocampal neurogenesis...... These mouse studies in this post also seem promising.

Could somewhat simple one-time fecal transplant prevent decline in those with 1 or 2 copies of Apoe4? Thoughts or new findings???
Hi FamilyHistory,
Thank you for posting the links to these studies. Impressive results!
I am happy that you have resurrected this thread which has been dormant since 2019. At one point a few years ago, after following a diet that eliminated many foods, I tested my microbiome through Viome. I was shocked to find that I was in the lowest 11th pércentile for microbiome diversity. A year later, after re-diversifying my diet, my microbiome had recovered and was in the 95th percentile. Since then, I haven’t tested.
I don’t have any new findings to report, but your post will definitely get me looking for what other recent information may be available. If I find anything that adds to the discussion, I’ll post it here. I hope you’ll do the same. Meanwhile,, I’m wondering: Do you think for prevention it may be sufficient to eat a diet that supports a healthy microbiome? Or would there be an advantage to the fecal transplant?
I understand that for the studies, something that immediately changes the microbiome is necessary to show the causal effect. But for us, maybe just keeping an eye on our microbiomes and encouraging diversity is enough. What do you think?
Functional Medicine Certified Health Coach
IFM/ Bredesen Training in Reversing Cognitive Decline (March 2017)
ReCODE 2.0 Health Coach with Apollo Health
NF52
Support Team
Support Team
Posts: 2953
Joined: Tue Oct 25, 2016 9:41 am
Location: Eastern U.S.

Re: Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by NF52 »

FamilyHistory wrote: Sat Jun 08, 2024 5:14 pm Since Alzheimer's has also causal factors in the gut microbiome, this promising fecal implant for Parkinson's symptomatic improvement, https://www.thelancet.com/journals/ecli ... 1/fulltext, and the reverse (fecal implant from humans with Alzheimer's causes cognitive decline and biomarkers in rats https://academic.oup.com/brain/article/ ... ogin=false ), this approach gives me possible hope for fecal implant treatment to improve hippocampal neurogenesis...... These mouse studies in this post also seem promising.

Could somewhat simple one-time fecal transplant prevent decline in those with 1 or 2 copies of Apoe4? Thoughts or new findings???
Welcome to the forum, "FamilyHistory",

Given your username, I am taking a mild leap in assuming you have a family history of Alzheimer's and/or other neurological disorders, and either one or two copies of ApoE4. If so, you and I have both of those things in common, and you have the edge on me in reading one of the Lancet's e-journals on Clinical Medicine to find this intriguing, open-access article from very recent research.

High levels of cognitive reserve (high education, high occupational challenge, intellectual curiosity) have repeatedly been shown to correlate strongly with cognitive resistance to the genetic risks of ApoE 4. You're showing all of that and raising thought-provoking questions !

Because this topic may get a lot of interest, I'm going to use your link to share some of what the study had to say. Sharing studies and discussing their potential impact is a favorite pastime on the forum and one I hope you will continue to join in on!

For those whose family history does not include Parkinson's, here's a brief overview from the article about their reasoning, with emphasis added:
The pathological hallmark of PD, alpha-synuclein aggregates, has been observed in the gastrointestinal system during the prodromal phase of the disease. This aggregated alpha-synuclein can reach the brain via the vagal nerve, which has been shown directly in animal models and indirectly by an apparent reduced risk of developing PD after vagotomy. These findings led to the dual-hit Braak hypothesis which states that alpha-synuclein aggregation is triggered by microbiota at the level of the gut and/or the olfactory nerves. Recently, this hypothesis has been expanded to a body-first or brain-first onset of PD. In the body-first phenotype, pathology is believed to start in the gut and emerging evidence suggests that the gut microbiome may play this pivotal role in PD pathogenesis and progression.
Below is an excerpt of the results in a group of 21 patients who received health donor microbiota vs. 22 people with similar disease stage who received a "placebo" treatment of their own donated microbiota. {Everyone donated their own stool, so both participants and investigators were "blinded" as to who received which treatment, similar to current anti-amyloid drug infusions of a drug or a saline solution.
At the 12-month mark, the primary outcome measure, namely the MDS-UPDRS motor scores in an off-medication state, showed improvement in the healthy donor FMT group with a decrease of 5.8 points (95% CI −11.4 to −0.2) compared to 2.7 points (−8.3 to 2.9) in the placebo group (Table 2; Fig. 2). The change in MDS-UPDRS motor score from baseline to 12 months post-FMT was significantly different between treatment groups (p = 0.0235; Table 2; Fig. 2), with the most important between-group deviation in the 6-to-12-months interval. The placebo FMT group experienced an increase in the number of radiopaque pellets by 6.9 pellets (2.0–11.8) corresponding to an increased colon transit time, whereas the active treatment group had a small decrease of 1.2 pellets (−6.1 to 3.7) (p = 0.0252; Table 3; Fig. 3).

Additionally, the healthy donor FMT group demonstrated worse performance on the Parkinson's Fatigue Scale (p = 0.0418; Table 3). There were no significant differences between the treatment groups in other scores of the MDS-UPDRS (part 1, part 2, part 4, and part 1–4 total score; Table 2), the LEDD, the Non-Motor Symptoms Scale for Parkinson's Disease, the Parkinson's Disease Quality of Life Questionnaire, Wexner Constipation Scale, Geriatric Depression Scale, Parkinson Anxiety Scale, Lille Apathy Rating Scale, Parkinson's Disease Sleep Scale, and Montreal Cognitive Assessment (Table 3).
Most Phase 1-2 trials want to see if a treatment is safe first of all, and if it shows indications of benefit on a meaningful and measurable "primary outcome". Often several other "secondary outcomes" are also studied in hopes of seeing some "signal' of an effect, but recognizing that those areas, especially if they involve behavioral or daily living skills, often change slowly in the normal course of events.

Often the small numbers of people in an early trial don't allow for terms like "statistically significant", which require sometimes hundreds or thousands of people. This study was well-designed to have enough people to find a trend towards a meaningful benefit in a PD motor score--and it looks like it shows that trend, with only about 2% likelihood that the results were due to chance. But other aspects of PD, probably as expected, didn't show a change.

Having had a maternal uncle with Parkinson's with dementia, and a mother and several maternal aunts with Alzheimer's and/or vascular dementia, I think the possible links of ApoE 4 to both are worth studying! It remains to be seen if alpha-synuclein, the signature mis-folded protein of PD and Lewy Body Dementia, is the only mis-folded protein that can reach the brain through the vagus nerve, or if other forms of GI inflammation can be treated in people at genetic risk of AD and reduce or prevent amyloid plaques and tau tangles. I hope this article in a journal with the impact of the Lancet drives some more funding towards this hypothesis!

In case you are looking for broader overviews of the strategies used by many on the forum, the Primer written by Stavia, a practicing M.D. with ApoE4/4, is a great resource. She has a bibliography at the end of her index of strategies with possible biomarkers to monitor.

The How-To Guide shows how to quote members (use the " icon in the upper right of any post) so they get an email notification of your post. It also shows how to use the Search function for topics, and how to subscribe to topics of interest.

And if you'd like to share more of the family history and scientific curiosity and acumen that led you here, feel free to post on Our Stories.

Nancy
4/4 and still an optimist!
FamilyHistory
New User
New User
Posts: 2
Joined: Sun Jun 11, 2023 12:38 pm

Re: Fecal microbiota transplantation alleviated Alzheimer's disease-like pathogenesis in APP/PS1 transgenic mice

Post by FamilyHistory »

Thank you, Nancy and floramaria for your engagement and resources, encouragement and optimism !!

Re: finding these articles, I saw the study as the lead story in the Brainhealth Breakthroughs Newsletter and then looked a bit further.

To answer one of floramaria's questions, I think it makes sense to pay attention to diversity of the gut biome, but if noticing subjective symtpoms, wouldn't it make sense to do a one-time transplant to stop the process?? It seems like such an elegant solution; I wish a lab would do this study, even in mice or rats.....
Post Reply