Microbial BMAA elicits mitochondrial dysfunction, innate immunity activation, and Alzheimer’s disease features in cortical neurons

Abstract

Background After decades of research recognizing it as a complex multifactorial disorder, sporadic Alzheimer’s disease (sAD) still has no known etiology. Adding to the myriad of different pathways involved, bacterial neurotoxins are assuming greater importance in the etiology and/or progression of sAD. β-N-Methylamino-l-alanine (BMAA), a neurotoxin produced by some microorganisms namely cyanobacteria, was previously detected in the brains of AD patients. Indeed, the consumption of BMAA-enriched foods has been proposed to induce amyotrophic lateral sclerosis-parkinsonism-dementia complex (ALS-PDC), which implicated this microbial metabolite in neurodegeneration mechanisms. Methods Freshly isolated mitochondria from C57BL/6 mice were treated with BMAA and O2 consumption rates were determined. O2 consumption and glycolysis rates were also measured in mouse primary cortical neuronal cultures. Further, mitochondrial membrane potential and ROS production were evaluated by fluorimetry and the integrity of mitochondrial network was examined by immunofluorescence. Finally, the ability of BMAA to activate neuronal innate immunity was quantified by addressing TLRs (Toll-like receptors) expression, p65 NF-κB translocation into the nucleus, increased expression of NLRP3 (Nod-like receptor 3), and pro-IL-1β. Caspase-1 activity was evaluated using a colorimetric substrate and mature IL-1β levels were also determined by ELISA. Results Treatment with BMAA reduced O2 consumption rates in both isolated mitochondria and in primary cortical cultures, with additional reduced glycolytic rates, decrease mitochondrial potential and increased ROS production. The mitochondrial network was found to be fragmented, which resulted in cardiolipin exposure that stimulated inflammasome NLRP3, reinforced by decreased mitochondrial turnover, as indicated by increased p62 levels. BMAA treatment also activated neuronal extracellular TLR4 and intracellular TLR3, inducing p65 NF-κB translocation into the nucleus and activating the transcription of NLRP3 and pro-IL-1β. Increased caspase-1 activity resulted in elevated levels of mature IL-1β. These alterations in mitochondrial metabolism and inflammation increased Tau phosphorylation and Aβ peptides production, two hallmarks of AD. Conclusions Here we propose a unifying mechanism for AD neurodegeneration in which a microbial toxin can induce mitochondrial dysfunction and activate neuronal innate immunity, which ultimately results in Tau and Aβ pathology. Our data show that neurons, alone, can mount inflammatory responses, a role previously attributed exclusively to glial cells.

BMAA, Methylmercury, and Mechanisms of Neurodegeneration in Dolphins: A Natural Model of Toxin Exposure

“…However, the presence of both toxins suggests a synergistic or, at minimum, additive potential to induce neurodegeneration. Possible mechanisms of combined toxicity may include both BMAA’s and MeHg’s ability to cause glutathione depletion, glutamate dyshomeostasis, mitochondrial dysfunction, and the stimulation of the unfolded protein response [ 15 , 44 , 68 , 69 , 70 , 71 ].…”

Footprints of a microbial toxin from the gut microbiome to mesencephalic mitochondria

“…Evidence suggests that BMAA can be misincorporated in proteins in place of serine, or bind electrostatically to protein nascent chains causing misfolding, aggregation, endoplasmic reticulum (ER) stress and apoptosis 19. Moreover, BMAA can induce mitochondrial dysfunction interfering with oxidative phosphorylation while also deregulating calcium homoeostasis and leading to reactive oxygen species (ROS) overproduction 21. Although there is still no evidence that members of the gut microbiota can produce BMAA, hypermethylation of cg06690548 on chromosome 4 in the promoter of SLC7A11 gene in PD patients is associated with downregulation of this cysteine–glutamate antiporter, a known target of BMAA,22 which is argued to be consistent with a PD-related environmental exposure.…”

iTRAQ‐Based Quantitative Proteomics Indicated Nrf2/OPTN‐Mediated Mitophagy Inhibits NLRP3 Inflammasome Activation after Intracerebral Hemorrhage

“…Besides, mitochondrial dysfunction-induced abnormal OXPHOS activity and mtDNA damage also lead to the activation of NLRP3 inflammasome [ 17 ]. Thus, mitochondrial dysfunction is the upstream core event that leads to the activation of NLRP3 inflammasome, which has been proven in several central nervous system diseases, such as Parkinson's disease [ 47 , 48 ], postoperative cognitive dysfunction [ 49 ], cerebral ischemia-reperfusion injury [ 50 , 51 ], and Alzheimer's disease [ 52 ], while it is not clear whether this activation mechanism also exists in ICH. Prior studies have shown that the mitochondrial respiratory chain and mitochondrial membrane potential were abnormal in the brain tissue surrounding hematoma and closely associated with SBI after ICH [ 53 , 54 ].…”