Abstract
BackgroundNeurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. Infectious agent-derived pathogen-associated molecular patterns (PAMPs) activate microglia, key players in neurodegenerative diseases. We hypothesized that systemic microbial pathogens may accelerate neurodegeneration in Alzheimer’s disease (AD) and that microglia play a central role in this process.MethodsWe examined the effect of an infectious environment and of microbial Toll-like receptor (TLR) agonists on cortical neuronal loss and on microglial phenotype in wild type versus 5xFAD transgenic mice, carrying mutated genes associated with familial AD.ResultsWe examined the effect of a naturally bred environment on the neurodegenerative process. Earlier and accelerated cortical neuron loss occurred in 5xFAD mice housed in a natural (“dirty”) environment than in a specific-pathogen-free (SPF) environment, without increasing the burden of Amyloid deposits and microgliosis. Neuronal loss occurred in a microglia-rich cortical region but not in microglia-poor CA regions of the hippocampus. Environmental exposure had no effect on cortical neuron density in wild-type mice. To model the neurodegenerative process caused by the natural infectious environment, we injected systemically the bacterial endotoxin lipopolysaccharide (LPS), a TLR4 agonist PAMP. LPS caused cortical neuronal death in 5xFAD, but not wt mice. We used the selective retinoic acid receptor α agonist Am580 to regulate microglial activation. In primary microglia isolated from 5xFAD mice, Am580 markedly attenuated TLR agonists-induced iNOS expression, without canceling their basic immune response. Intracerebroventricular delivery of Am580 in 5xFAD mice reduced significantly the fraction of (neurotoxic) iNOS + microglia and increased the fraction of (neuroprotective) TREM2 + microglia. Furthermore, intracerebroventricular delivery of Am580 prevented neurodegeneration induced by microbial TLR agonists.ConclusionsExposure to systemic infections causes neurodegeneration in brain regions displaying amyloid pathology and high local microglia density. AD brains exhibit increased susceptibility to microbial PAMPs’ neurotoxicity, which accelerates neuronal death. Microglial modulation protects the brain from microbial TLR agonist PAMP-induced neurodegeneration.
Highlights
Neurodegeneration is considered the consequence of misfolded proteins’ deposition
In 5xFAD mice, the transgenic cassette is expressed under the Thy1.1 promoter, and the Alzheimer’s disease (AD) pathology is disseminated throughout the cortex, rather than being localized to the Hippocampus, as occurs in the early stages of the classical amnestic form of human AD [31,32]
To confirm that the immune-modulatory effect of Am580 was not restricted to TLR4 activation, we examined whether Am580 affects microglial activation in response to a TLR2 agonist
Summary
Neurodegeneration is considered the consequence of misfolded proteins’ deposition. Little is known about external environmental effects on the neurodegenerative process. The neurodegenerative process in Alzheimer’s disease (AD) is considered the consequence of deposition of misfolded amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) proteins [1], with histopathological hallmarks that include Aβ-rich extracellular plaques, p-tau-rich neurofibrillary tangles, microgliosis, astrogliosis, and neuronal loss. Systemic infections are associated with long-lasting cognitive decline in patients with pre-existing AD [2,3]. It is not clear whether and how systemic infections affect the neurodegenerative process itself. Endotoxin has been shown to exacerbate brain pathology in animal models, and Aβ production and aggregation [8] and Tau hyperphosphorylation [8,9]. People with chronic gingival disease (periodontitis) have elevated blood endotoxin [13], a higher risk of AD [14], and a faster rate of cognitive decline [13,15,16]
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