Alterations in the Gut-Microbial-Inflammasome-Brain Axis in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory loss and cognitive decline, is a major cause of death and disability among the older population. Despite decades of scientific research, the underlying etiological triggers are unknown. Recent studies suggested that gut microbiota can influence AD progression; however, potential mechanisms linking the gut microbiota with AD pathogenesis remain obscure. In the present study, we provided a potential mechanistic link between dysbiotic gut microbiota and neuroinflammation associated with AD progression. Using a mouse model of AD, we discovered that unfavorable gut microbiota are correlated with abnormally elevated expression of gut NLRP3 and lead to peripheral inflammasome activation, which in turn exacerbates AD-associated neuroinflammation. To this end, we observe significantly altered gut microbiota compositions in young and old 5xFAD mice compared to age-matched non-transgenic mice. Moreover, 5xFAD mice demonstrated compromised gut barrier function as evident from the loss of tight junction and adherens junction proteins compared to non-transgenic mice. Concurrently, we observed increased expression of NLRP3 inflammasome and IL-1ß production in the 5xFAD gut. Consistent with our hypothesis, increased gut-microbial-inflammasome activation is positively correlated with enhanced astrogliosis and microglial activation, along with higher expression of NLRP3 inflammasome and IL-1ß production in the brains of 5xFAD mice. These data indicate that the elevated expression of gut-microbial-inflammasome components may be an important trigger for subsequent downstream activation of inflammatory and potentially cytotoxic mediators, and gastrointestinal NLRP3 may promote NLRP3 inflammasome-mediated neuroinflammation. Thus, modulation of the gut microbiota may be a potential strategy for the treatment of AD-related neurological disorders in genetically susceptible hosts.

DNA Double-Strand Break Accumulation in Alzheimer's Disease: Evidence from Experimental Models and Postmortem Human Brains.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for a majority of dementia cases. AD is characterized by progressive neuronal death associated with neuropathological lesions consisting of neurofibrillary tangles and senile plaques. While the pathogenesis of AD has been widely investigated, significant gaps in our knowledge remain about the cellular and molecular mechanisms promoting AD. Recent studies have highlighted the role of DNA damage, particularly DNA double-strand breaks (DSBs), in the progression of neuronal loss in a broad spectrum of neurodegenerative diseases. In the present study, we tested the hypothesis that accumulation of DNA DSB plays an important role in AD pathogenesis. To test our hypothesis, we examined DNA DSB expression and DNA repair function in the hippocampus of human AD and non-AD brains by immunohistochemistry, ELISA, and RT-qPCR. We observed increased DNA DSB accumulation and reduced DNA repair function in the hippocampus of AD brains compared to the non-AD control brains. Next, we found significantly increased levels of DNA DSB and altered levels of DNA repair proteins in the hippocampus of 5xFAD mice compared to non-transgenic mice. Interestingly, increased accumulation of DNA DSBs and altered DNA repair proteins were also observed in cellular models of AD. These findings provided compelling evidence that AD is associated with accumulation of DNA DSB and/or alteration in DSB repair proteins which may influence an important early part of the pathway toward neural damage and memory loss in AD.

Touchscreen tasks in mice to demonstrate differences between hippocampal and striatal functions.

In mammals, hippocampal and striatal regions are engaged in separable cognitive processes usually assessed through species-specific paradigms. To reconcile cognitive testing among species, translational advantages of the touchscreen-based automated method have been recently promoted. However, it remains undetermined whether similar neural substrates would be involved in such behavioral tasks both in humans and rodents. To address this question, the effects of hippocampal or dorso-striatal fiber-sparing lesions were first assessed in mice through a battery of tasks (experiment A) comprising the acquisition of two touchscreen paradigms, the Paired Associates Learning (dPAL) and Visuo-Motor Conditional Learning (VMCL) tasks, and a more classical T-maze alternation task. Additionally, we sought to determine whether post-acquisition hippocampal lesions would alter memory retrieval in the dPAL task (experiment B). Pre-training lesions of dorsal striatum caused major impairments in all paradigms. In contrast, pre-training hippocampal lesions disrupted the performance of animals trained in the T-maze assay, but spared the acquisition in touchscreen tasks. Nonetheless, post-training hippocampal lesions severely impacted the recall of the previously learned dPAL task. Altogether, our data show that, after having demonstrated their potential in genetically modified mice, touchscreens also reveal perfectly adapted to taxing functional implications of brain structures in mice by means of lesion approaches. Unlike its human counterpart requiring an intact hippocampus, the acquisition of the dPAL task requires the integrity of the dorsal striatum in mice. The hippocampus only later intervenes, when acquired information needs to be retrieved. Touchscreen assays may therefore be suited to study striatal- or hippocampal-dependent forms of learnings in mice.