Loose Ends of the Alzheimer Disease Enigma

This fascinating article recently appeared in Science Magazine: ApoE isoform– and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy.

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It begins to tie together several loose ends of the Alzheimer Disease enigma. The prevailing amyloid hypothesis posits that Aβ plaques are the major cause of AD. Indeed, two recent anti-amyloid drugs have been approved by the FDA – yet, with small, possibly insignificant, clinical benefit.

P301S tau transgenic mice expressing human APOE (TE mice). The dysregulated gut-brain axis and its effect on tauopathy and tau-mediated neurodegeneration. Dysbiosis, unbalanced gut microbiota composition (bottom center), contributes to tau-mediated neurodegeneration by generating bacterial metabolites (e.g., SCFAs) that influence peripheral immune cells. These cells promote central nervous system (CNS) inflammation and contribute to tau aggregation and neurodegeneration. Short-term antibiotics (bottom right) or germ-free conditions (bottom left) reshape or eliminate gut microbiota and reduce their metabolites. These microbiota manipulations influence effects of peripheral immune cells on CNS inflammation and tau-mediated neurodegeneration. ApoE4 in the CNS exacerbates local toxicity and blood-brain barrier dysfunction.

Other causative factors, including tau protein and inflammation via microglia activation, are drawing evermore increasing attention. The current article adds to the mix yet another hot scientific topic: the gut microbiome. The investigators demonstrate the relationship between the gut microbiota, tau, and brain inflammation in a mouse tauopathy model expressing ApoE3 and ApoE4. Strikingly, antibiotic manipulation of the gut microbiota resulted in a notable reduction in tau pathology and neurodegeneration, including milder hippocampal atrophy compared to controls and reduced phosphorylated tau protein. Short-chain fatty acids are suggested to mediate the sequence from neuroinflammation to neurodegeneration.

Is the human gut microbiota the central unexpected factor in Azheimer disease? Only time and newly focussed research will tell. PET imaging of tau, Aβ, and activated microglia can play an ever increasing role in this new endeavor as human gut microbiota manipulations and treatments are investigated. One wonders whether PET molecular imaging of the gut microbiome could be developed in this ever intriguing effort to solve the Azheimer disease problem.

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