FSB presentation

FSB presentation:

Analysing implications of the gut microbiome in Alzheimer’s disease and the associated frontier of therapeutic strategies.

Freya Sanctuary

index

09. Enzyme intervention?

05. Model organisms

01. Why AD?

02. AD overview

06. Gram-negative taxa

10. Probiotic intervention?

11. Conclusions

07. Proposed mechanism

03. GMB overview

04. What is the GBA?

12. Questions...

08. FMT intervention?

01. Why Ad?

Alzheimer's disease (AD) is a neurodegenerative disease

55 million people with dementia world wide 70% of these have AD Leading cause of death in England and Wales in 2022 (11.4%) Estimated costs $1.3 trillion in 2019 Costs predicted to reach $2.8 trillion by 2030 Psychological toll on relatives & caregivers No cure despite millions invested in research annually.

02. AD overview

consequences:

• Mitochondrial damage
• Oxidative stress

• Apoptosis

• Microglia activation
• Phagocytosis
• Immune response (chronic)
• Neuroinflammation

Decline to motor skills, memory, language, and behaviour.

Characterised by Aβ plaques and neurofibrillary tangles (NFT). Amyloid precursor protein (unknown function) is processed by secretases and peptides Aβ40 and Aβ42 are formed.

Neurofibrillary tangles are composed of hyperphosphorylated Tau protein. Likely Aβ forms before NFT formation in AD... ...NFT formation occurs in normally ageing people, independent of Aβ plaques.

Molecular basis:

03. GMB overview

Humans have a mutualistic relationship with The gut microbiome (GMB)

Complex and dynamic community Mainly bacteria, but also archaea, fungi, and viruses. Established by 2 years of age Influenced by diet, antibiotics, genetics Impacts physiology- health and disease.

• Digestion & nutrient absorption
• Immune function
• Metabolism & weight
• Mental health
• Inflammation
• Vitamin production
• Drug metabolism

04. What is the GBA?

"the great abdominal brain" (18th Century)

Conceptual channel between the cerebral and enteric NS Likley mediated by the vagus nerve, gut-produced hormones, and microbial metabolites

- Vagotomised mice (Bravo et al, 2011).

Implicated in many neurological conditions Microbial changes, intestinal permeability, sensory afferents, neuroactive molecules, immune responses, etc.

- Anxiety, depression, ASD, Parkinson's

Implicated in neurodegenerative disorders like AD...

05. model organisms

Flies

Fantastic ameanability to genetic modification Conservation of key pathways and regulators Homologs to 70% of human disease genes. Relatively simple gut microbial composition Serotonergic cluster afferent to the gut; functional similarity to vagus nerve. Behavioural changes easily measured.

05. model organisms

Mice

Mirror human gut anatomy Microbial composition is similar Comprehensive understanding of mice genetics Availability of many mouse models Mammalian brain Can generate germ-free mice or microbiome depeleted mice Behavioural changes are easy to measure.

06. Gram-negative bacteria

Anti-microbial peptides are found in the gut and brain of AD patients

• Flies = Immune deficiency (IMD)
• Mammals = Toll-like receptor

AMPs defend against pathogenic microbes.Pathway responsible for AMP synthesis is conserved in across metazoa = NFkB

• Improved lifespan
• Reversal of learning deficits
• Reduced Aβ accumulation in the brain
• Reduced ROS in the gut and brain
• Improved gut integrity.

Hseih and Chian (2023)

Upregulating AMPs that target gram-negative bacteria reduced AD pathologies - Attacin-A (AttA) and Dpitercin-A (DptA) Used an anti-gram-negative antibiotic to corroborate results. Can conclude a pathological correlation to gram-negative bacteria.

Intestinal AttA reduces oxidative stress in gut and brain

DptA improved learning performance

AttA reduces Aβ accumulation in brain

06. Gram-negative bacteria

Used an antibiotic against gram-negative bacteria to corroborate results (Apramycin)

Hseih and Chian (2023)

Apramycin reduces Aβ-induced oxidative stress in the gut but not brain.

Apramycin improved learning performance

Data are represented as mean ± SEM. Two-way ANOVA followed by multiple comparisons

Dysregulated gram-negative bacteria in the gut results in oxidative stress Intestinal AMPs are relevant for mediating disease

07. a proposed mechanism

gram-negative taxa activates transcription factors

(Chen et al, 2022)

Studies show that the AD GMB stimulates a pathway called C/EBPβ/AEP = activates expression of AEP (γ-secretase) = responsible for cleavage of APP and Tau

Express this pathway in mice neurons (Thy1-C/EBPβ)...

• Widespread Aβ deposition,
• Significant elevation of Aβ42 in the brain
• Tau accumulation in the hippocampus
• Significant synapse reduction
• Cognitive deficit.

(Xia et al, 2023)

• Exposure of Bacteroides fragilis lead to AD-like pathology

• Increased C/EBPβ expression and strong microglia activation

• Also enhanced the metabolism of Arachidonic acid (AA)

By COX1/2 to form PUFA metabolites = 12-HHTrE and PGE2

Treatment with these metabolites recapitulated results generated by B. fragilis = increased C/EBPβ expression, strong microglia activation, increased Aβ deposition, increased Aβ42 production, increased proinflammatory cytokines, cognitive deficits

07. a proposed mechanism

(Xia et al, 2023)

Treatment with these metabolites recapitulated results generated by B. fragilis = increased C/EBPβ expression, strong microglia activation, increased Aβ deposition, increased Aβ42 production, increased proinflammatory cytokines, cognitive deficits

Suggesting gram-negative bacteria exerts C/EBPβ/AEP signalling and microglia activation by 12-HHTrE and PGE2.

Cycle of neuroinflammation...

C/EBPβ is activated by pro-inflammatory cytokines and also controls COX enzyme expression. In turn AA metabolism is upregulated; increasing PUFA metabolites 12-HHTrE and PGE2. Feedback to activate more microglia and exacerbating neuroinflammation.

Interventions...

20+ years of researching potential targets of the amyloid cascade has been fruitless

Enzymes

What are the potential therapies for AD that utilise our developing knowledge on the GMB?

FMT

Probiotics

08. FMT intervention?

Faecal microbiota transplant (FMT) is able to modulate the GMB..

Already succesfully used in GI disorders (Eg- Chrohn's disease), and also used in research to study effects of a dysregulated GMB in wt animals.

• Transplanting faecal matter from a wt donor to AD-model mice.
• Reversed changes to the GMB composition
• Relieved AD pathology

(Sun et al, 2019)

• Cognitive improvement
• Reduced Aβ deposition and Tau phosphorylation in the brain
• Decreased pro-inflammatory markers and neuroinflammation

Considerations

• Sun's AD-mice had decreased Bacteroidetes populations then reversed by FMT; this phylum is typically abundant in AD and its members contribute to AD pathology...
• Variability of results between individuals
• Reports of immune deficiencies following FMT
• Side-effects?

09. Enzyme intervention?

Enzyme replacement therapy is widely used to treat symptoms of late-stage chronic pancreatitis- likely by altering GMB composition. (Nishiyama et al, 2018)

Disrupted lipid homeostasis is implicated in AD...

• Candida rugosa lipase (CRL) treatment is able to alter GMB composition, reduce microgliosis, and improve learning performance.

• Preventing the increase in elevation of unsaturated fatty acids seen in untreated AD-models.

• FMT into GMB-depleted mice showed memory improvement when AD-model faecal donor was treated with CRL

(Menden et al, 2022)

???

The lipase activity increased the variety of fatty acids... 1- Altering the GBM to normalise levels of fatty acids thereby decreasing oxidative stress and gliosis 2- Stimulating vagal signalling via enteric afferents projecting to the brain causing reprogramming of microglia

10. probiotic intervention?

(Huang et al, 2021)

• Use of probiotic called Lactobacillus plantarum PS128

• Used AD-models + diabetogenic toxin that accelerates AD progression

• Half the models were treated with PS128 and the development of pathologies was measured.

• Was able to prevent AD-pathologies seen in untreated AD models

Prevented increased number of activated microglia, neurodegeneration, cognitive decline, Aβ deposition

Considerations.

• Mechanisms of actions not understood
• Founded on correlative research
• Human GMB is more complex than any model
• Side effects?

= deeper probiotic research is needed to properly evaluate its therapeutic potential.

11. Conclusions

Microbiome research for neurodegenerative disorders represents a cutting-edge side of biology.

• The microbiome mediates many physiological aspects
• AD pathologies are correlated with gram-negative bacteria
• How the microbiome actions its affects is largely unknown
• Many factors within AD pathology- issue of causality
• One proposed mechanism for the microbiome in AD involves activation of signalling molecules and microglia

• Recent years have produced potential therapeutic avenues in research- need mechanistic detail before clinical appliation may be considered.

Questions?

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