[Paper Review] Title: Reduction of Alzheimer's disease beta-amyloid pathology in the absence of gut microbiota

Taoufiq Harach, Nittaya Marungruang+8 more|arXiv (Cornell University)|Sep 8, 2015

Gut microbiota and health21 references21 citations

TL;DR

This study demonstrates that germ-free Alzheimer's disease (AD) mice exhibit drastically reduced beta-amyloid (Ab) pathology compared to conventionally raised AD mice with intact gut microbiota. Using germ-free AD mouse models and fecal microbiota transplantation, the researchers found that microbiota from AD mice, but not from healthy wild-type mice, significantly increased cerebral Ab plaque deposition, implicating gut microbiota in promoting AD pathology through microbial modulation of amyloid burden.

ABSTRACT

Alzheimer's disease is the most common form of dementia in the western world, however there is no cure available for this devastating neurodegenerative disorder. Despite clinical and experimental evidence implicating the intestinal microbiota in a number of brain disorders, its impact on Alzheimer's disease is not known. We generated a germ-free mouse model of Alzheimer's disease and discovered a drastic reduction of cerebral Ab amyloid pathology when compared to control Alzheimer's disease animals with intestinal microbiota. Sequencing bacterial 16S rRNA from fecal samples revealed a remarkable shift in the gut microbiota of conventionally-raised Alzheimer's disease mice as compared to healthy, wild-type mice. Colonization of germ-free Alzheimer mice with harvested microbiota from conventionally-raised Alzheimer mice dramatically increased cerebral Ab pathology. In contrast, colonization with microbiota from control wild-type mice was ineffective in increasing cerebral Ab levels. Our results indicate a microbial involvement in the development of Alzheimer's disease pathology, and suggest that microbiota may contribute to the development of neurodegenerative diseases.

Motivation & Objective

• To investigate the role of gut microbiota in the development of Alzheimer's disease (AD) pathology.
• To determine whether the absence of gut microbiota alters the progression of amyloid-beta (Ab) plaque deposition in AD mouse models.
• To assess the impact of microbiota transplantation from AD mice versus healthy wild-type mice on cerebral Ab pathology.
• To explore whether microbial communities in the gut contribute to neuroinflammatory or neurodegenerative processes in AD.

Proposed method

• Generation of germ-free Alzheimer's disease mouse models to eliminate endogenous gut microbiota.
• Comparison of cerebral beta-amyloid (Ab) pathology between germ-free AD mice and conventionally raised AD mice with intact microbiota.
• 16S rRNA sequencing of fecal samples to profile gut microbial composition in AD and wild-type mice.
• Fecal microbiota transplantation (FMT) from conventionally raised AD mice into germ-free AD mice to assess pathological impact.
• FMT from healthy wild-type mice into germ-free AD mice as a negative control to test specificity of microbiota effects.
• Quantitative assessment of Ab plaque burden in the brain using histological or immunohistochemical methods.

Experimental results

Research questions

• RQ1 Does the absence of gut microbiota reduce beta-amyloid plaque deposition in Alzheimer’s disease mouse models?
• RQ2 How does the gut microbiota composition differ between Alzheimer’s disease mice and healthy wild-type mice?
• RQ3 Can fecal microbiota transplantation from AD mice into germ-free AD mice restore or increase cerebral Ab pathology?
• RQ4 Does microbiota from healthy wild-type mice induce Ab pathology in germ-free AD mice?
• RQ5 To what extent does gut microbiota modulate the progression of Alzheimer’s disease pathology in vivo?

Key findings

• Germ-free Alzheimer’s disease mice exhibited a drastic reduction in cerebral beta-amyloid (Ab) pathology compared to conventionally raised AD mice with intact gut microbiota.
• 16S rRNA sequencing revealed a significant shift in gut microbiota composition in conventionally raised AD mice compared to healthy wild-type mice.
• Fecal microbiota transplantation from conventionally raised AD mice into germ-free AD mice dramatically increased cerebral Ab pathology.
• Transplantation of microbiota from healthy wild-type mice into germ-free AD mice failed to increase cerebral Ab levels.
• The results indicate that specific microbial communities from AD-affected mice promote Ab plaque deposition, while those from healthy mice do not.
• These findings suggest a causal role for gut microbiota in the development of Alzheimer’s disease pathology, particularly amyloid burden.