We now believe that amyloid-β, tau, and apolipoprotein E (APOE) are involved in the pathogenesis of Alzheimer's disease (in a way that is not yet fully understood). Recently, reports have been accumulating that gut bacteria are involved in brain changes induced by these proteins. Dong-Oh Seo and colleagues from David Holtzman's lab at Washington University School of Medicine in St. Louis, MO, USA, have now been able to show in a paper published earlier this year in Science that tau-mediated neurodegeneration in Alzheimer's mice is negatively affected by the microbiome. In animals raised either conventionally or under germ-free conditions, they convincingly demonstrate that gut bacteria play a causative role in tau-mediated neurodegeneration by enhancing inflammatory processes in the periphery and brain.
Short-chain fatty acids produced by the bacteria stimulate inflammatory processes that promote tau-initiated mechanisms in an APOE isoform-dependent and sex-specific manner. Apparently, microbial metabolites activate peripheral immune cells, which in turn release cytokines that can then cross the blood-brain barrier and trigger neurodegeneration. Indeed, when Alzheimer's mice are raised under germ-free conditions, neuronal cell death and gliosis, or proliferation of astrocytes, do not occur.
Previous work has already suggested bacterial involvement in the development of Alzheimer's disease (AD), as treatment with antibiotics led to a reduction in Aβ pathology in an amyloid mouse model of Alzheimer's disease. The APOE4 variant is the strongest known genetic risk factor, whereas the APOE3 variant does not appear to affect AD risk. Interestingly, in the present work, the different APOE alleles resulted in different gut bacterial configurations.
Seo et al. used mouse strains carrying a mutant MAPT transgene encoding tau and different APOE3 or APOE4 variants and lived under sterile or conventional conditions. Remarkably, sterile conditions were strongly neuroprotective in male and female mice expressing APOE3 and APOE4. Brain matter loss was significantly reduced compared with animals that were first kept bacteria-free but then received fecal microbiota transplantation from sex-matched, conventionally raised APOE4 mice.
Could antibiotic treatment produce similar neuroprotective effects as germ-free rearing? Seo et al treated conventionally raised mice expressing mutant tau and APOE3, APOE4, or no APOE with an antibiotic cocktail and observed striking APOE isoform and sex-dependent effects: Absence of APOE resulted in minimal neurodegeneration. Male but not female mice of all APOE genotypes treated with antibiotics exhibited reduced tau levels as well as significant attenuation of brain atrophy and significant improvements in their (nestling) behavior. These results fit with previous data that long-term antibiotic treatment led to a reduction in Aβ pathology in male but not female mice (in an amyloid animal model). It appears that in addition to inflammatory mechanisms, sex hormones also play an important role in the development of the disease (see also my blog post of 3/30/2013).
So how exactly does the gut microbiota influence tau-mediated neurodegeneration? Seo et al. hypothesized that bacterial agents alter astrocytic and microglial responses in the context of neurodegeneration. Namely, they found decreased expression of gliosis markers in male animals kept free of bacteria. Differential gene expression analyses from the hippocampus of male mice indicated downregulation of innate immune response genes and glial activation in the absence of a normal microbiota. Similarly, antibiotic treatment induced changes in microglial and astrocyte gene expression, underscoring that the gut microbiota modulates glial responses.
An open question remains as to why the benefits of antibiotic treatment observed in APOE3 mice are not detectable in mice with APOE4, whereas a lifetime reduction in gut microbiota provides significant protection in both APOE3 and APOE4 mice. The underlying mechanism could be elucidated if the bacterial strains and short-chain fatty acids responsible for these differences are identified.
References:
Jain T, Li YM (2023) Gut microbes modulate neurodegeneration. Science 379:142
Seo DO, O'Donnell D, Jain N, Ulrich JD, ... , Gordon JI, Holtzman DM (2023) ApoE isoform- and microbiota-dependent progression of neurodegeneration in a mouse model of tauopathy. Science 379:eadd1236
Image credit: Dr_Microbe