Lactobacillus Eats Amyloid Plaque and Post-Biotically Attenuates Senescence Due to Repeat Expansion Disorder and Alzheimer's Disease

Abstract

Patients with Alzheimer's disease and related dementia (ADRD) are faced with a formidable challenge of focal amyloid deposits and cerebral amyloid angiopathy (CAA). The treatment of amyloid deposits in ADRD by targeting only oxidative stress, inflammation and hyperlipidemia has not yielded significant positive clinical outcomes. The chronic high-fat diet (HFD), or gut dysbiosis, is one of the major contributors of ADRD in part by disrupted transport, epigenetic DNMT1 and the folate 1-carbon metabolism (FOCM) cycle, i.e., rhythmic methylation/de-methylation on DNA, an active part of epigenetic memory during genes turning off and on by the gene writer (DNMT1) and eraser (TET2/FTO) and the transsulfuration pathway by mitochondrial 3-mercaptopyruvate sulfur transferase (3MST)-producing H₂S. The repeat CAG expansion and m⁶A disorder causes senescence and AD. We aim to target the paradigm-shift pathway of the gut-brain microbiome axis that selectively inhibits amyloid deposits and increases mitochondrial transsulfuration and H₂S. We have observed an increase in DNMT1 and decreased FTO levels in the cortex of the brain of AD mice. Interestingly, we also observed that probiotic lactobacillus-producing post-biotic folate and lactone/ketone effectively prevented FOCM-associated gut dysbiosis and amyloid deposits. The s-adenosine-methionine (SAM) transporter (SLC25A) was increased by hyperhomocysteinemia (HHcy). Thus, we hypothesize that chronic gut dysbiosis induces SLC25A, the gene writer, and HHcy, and decreases the gene eraser, leading to a decrease in SLC7A and mitochondrial transsulfuration H₂S production and bioenergetics. Lactobacillus engulfs lipids/cholesterol and a tri-directional post-biotic, folic acid (an antioxidant and inhibitor of beta amyloid deposits; reduces Hcy levels), and the lactate ketone body (fuel for mitochondria) producer increases SLC7A and H₂S (an antioxidant, potent vasodilator and neurotransmitter gas) production and inhibits amyloid deposits. Therefore, it is important to discuss whether lactobacillus downregulates SLC25A and DNMT1 and upregulates TET2/FTO, inhibiting β-amyloid deposits by lowering homocysteine. It is also important to discuss whether lactobacillus upregulates SLC7A and inhibits β-amyloid deposits by increasing the mitochondrial transsulfuration of H₂S production.

Keywords: ATP-citrate lyase; CAA; Piezo; RNA editor; eraser; folate 1-carbon metabolism; gene writer.

Figure 1

Chronic high fat dysbiosis diet leads to increase methionine and long-chain fatty acids (LCFA). This causes hyperhomocysteinemia (HHcy), lowers short chain fatty acids (SCFA), folate, ketone/lactone, hydrogen sulfide (H₂S). The probiotic lactobacillus reveres.

Figure 2

Schematics of how gut dysbiosis leads to epigenetic methylation alterations and causes Alzheimer’s disease (AD). ADAR, adenosine deaminase acting on RNA; CAG, cytidine-adenosine-guanidine), m¹A, methyl-1-adinosine; SAM, s-adenosine methionine; SAH, s-adenosine homocysteine; SAHH, s-adenosine homocysteine hydrolase; DNMT, DNA methyltransferase; TET, ten eleven translocators; HDAC, histone de-acetylase; SIRT, Histone-protein de-acetylase; H3K4, histone-3 lysine 4 [21,60,61].

Figure 3

Repeat nucleotide sequences (CAG) cause random mutations, leading to ALS and AD. The tannic acid inhibits transporter SLC25A and mitigates ALS and AD.

Figure 4

During ischemic conditions such as COPD, sleep apnea and decrease pulmonary function, initially mitochondrial synthesizes H₂S and coups with dys-bioenergetics. COPD, chronic obstructive pulmonary diseases; TCA, tri-carboxylic acid; CAT, cysteine transferase; 3MST, 3mercaprtopyruvate sulfotransferase; CBS, cystathionine beta transferase; Piezo, mechano-thermal Na/Ca/Mg and transient receptor potential receptor/channels.

Figure 5

The probiotics lactobacillus mitigates folate deficiency and improves mitochondrial pyruvates and H₂S levels, post-biotically. PCP, phosphatidylcartinine phosphatase; BHMT, betaine homocysteine methyl transferase.

Figure 6

The hypothesis is that the chronic gut-dysbiosis induces SLC25A, gene writer (DNMT1), HHcy and decreases gene eraser (TET2/FTO), leading to decrease SLC7A and mitochondrial transsulfuration H₂S production and bioenergetics. Lactobacillus, a tri-directional, folic acid (an inhibitor of beta amyloid deposits, reduces Hcy levels), and lactate ketone-body (fuel for mitochondria) producer increases SLC7A and H₂S production and inhibits amyloid deposits.