Brian Balin Philadelphia College of Osteopathic Medicine
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This is a very good paper offering further support for the role of infection-induced inflammation in triggering neurological impairment at the level of memory consolidation in the hippocampus. Interestingly, the authors obtained results indicating that the hippocampus of older animals as compared to that of young animals had elevated protein levels of IL-1β. Furthermore, the serum and another region of the brain, the parietal cortex, did not have elevated cytokine levels, and thus were comparable to the young infected animals in this regard. These data are consistent with other reports also showing the specific vulnerability of the normal aged hippocampus to peripheral challenge, especially with lipopolysaccharides (LPSs). So, the question becomes: What is happening in the older animals to increase their vulnerability to infectious challenge which leads to memory deficits? The authors suggest that this difference has its basis in the nature of the glial cells from young to old animals. In particular, they suggest that the old animals maintain “primed” glial cells that are neither resting nor activated, but upon peripheral infection, the glial cells become activated to produce exaggerated proinflammatory responses compared to young animals. This suggestion would implicate inflammation as the culprit in diminishing the memory capacity for older animals, and fits with existing paradigms in studies of neurodegeneration. However, there is still a void in our understanding of how specifically the brain’s glial cells become activated, and why this is occurring in specific brain regions.
One can speculate that this scenario may implicate the blood-brain barrier in old versus young animals, as well as in old versus young humans. What about fever generation in old versus young and increase in transient effects on the blood-brain barrier? Perhaps in old individuals, a greater length of time is required to clear the infection/LPS or reverse effects from the infection/LPS; thus, memory deficits will be more evident. Young animals may clear the infection much more efficiently than old because of a more prominent immune response. Older animals may demonstrate increased immunosenescence and clear the infection less efficiently. Receptor differences especially with regard to Toll-like receptors and their expression/sensitivity to LPS from old to young may play a significant role. Toll-like receptors would have a direct influence on how the endothelial cells and glial cells in the brain respond to systemic infectants and their products. In addition, systemic immune cells that are responding to infection and expressing integrins and adhesion molecules may also enter through the blood-brain barrier. This response may be quite different in young versus old animals, as well as in the different regions of the brain, for example, hippocampus versus parietal cortex.
Another question to ask would be: Why isn’t the proinflammatory cytokine level increased in serum and/or other brain regions? In the young animals, clearance of infection may be prominent and limit an extended proinflammatory response. In older animals, immunosenescence may limit the clearance of the infection, and the systemic proinflammatory response as well as that in the brain (e.g., microglial response) could be heightened with an increase in length of infection and localized response in the most vulnerable regions of the animals, namely, hippocampus.
With regard to neurodegeneration and Alzheimer disease, there could be both systemic and chronic infections that could act as stimuli for inflammation wherein the hippocampus would be the most vulnerable region of the brain to undergo early damage, eventually resulting in long-term change and neurodegeneration. Another question to address here is: What happens if the chronic stimulus enters the brain itself and is not cleared? In our work on Chlamydia pneumoniae and Alzheimer disease, as well as with the work of Itzhaki et al. (Herpes simplex virus I), and Miklossy et al. (Borrelia species), this scenario may be more likely. Thus, in both systemic as well as brain infections of older and aged individuals, the triggering of systemic and/or brain inflammatory responses may initiate structural and functional change in the brain, resulting in early damage, such as amyloid generation/deposition, that may precede and/or promote more extensive neurodegeneration.
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Philadelphia College of Osteopathic Medicine
This is a very good paper offering further support for the role of infection-induced inflammation in triggering neurological impairment at the level of memory consolidation in the hippocampus. Interestingly, the authors obtained results indicating that the hippocampus of older animals as compared to that of young animals had elevated protein levels of IL-1β. Furthermore, the serum and another region of the brain, the parietal cortex, did not have elevated cytokine levels, and thus were comparable to the young infected animals in this regard. These data are consistent with other reports also showing the specific vulnerability of the normal aged hippocampus to peripheral challenge, especially with lipopolysaccharides (LPSs). So, the question becomes: What is happening in the older animals to increase their vulnerability to infectious challenge which leads to memory deficits? The authors suggest that this difference has its basis in the nature of the glial cells from young to old animals. In particular, they suggest that the old animals maintain “primed” glial cells that are neither resting nor activated, but upon peripheral infection, the glial cells become activated to produce exaggerated proinflammatory responses compared to young animals. This suggestion would implicate inflammation as the culprit in diminishing the memory capacity for older animals, and fits with existing paradigms in studies of neurodegeneration. However, there is still a void in our understanding of how specifically the brain’s glial cells become activated, and why this is occurring in specific brain regions.
One can speculate that this scenario may implicate the blood-brain barrier in old versus young animals, as well as in old versus young humans. What about fever generation in old versus young and increase in transient effects on the blood-brain barrier? Perhaps in old individuals, a greater length of time is required to clear the infection/LPS or reverse effects from the infection/LPS; thus, memory deficits will be more evident. Young animals may clear the infection much more efficiently than old because of a more prominent immune response. Older animals may demonstrate increased immunosenescence and clear the infection less efficiently. Receptor differences especially with regard to Toll-like receptors and their expression/sensitivity to LPS from old to young may play a significant role. Toll-like receptors would have a direct influence on how the endothelial cells and glial cells in the brain respond to systemic infectants and their products. In addition, systemic immune cells that are responding to infection and expressing integrins and adhesion molecules may also enter through the blood-brain barrier. This response may be quite different in young versus old animals, as well as in the different regions of the brain, for example, hippocampus versus parietal cortex.
Another question to ask would be: Why isn’t the proinflammatory cytokine level increased in serum and/or other brain regions? In the young animals, clearance of infection may be prominent and limit an extended proinflammatory response. In older animals, immunosenescence may limit the clearance of the infection, and the systemic proinflammatory response as well as that in the brain (e.g., microglial response) could be heightened with an increase in length of infection and localized response in the most vulnerable regions of the animals, namely, hippocampus.
With regard to neurodegeneration and Alzheimer disease, there could be both systemic and chronic infections that could act as stimuli for inflammation wherein the hippocampus would be the most vulnerable region of the brain to undergo early damage, eventually resulting in long-term change and neurodegeneration. Another question to address here is: What happens if the chronic stimulus enters the brain itself and is not cleared? In our work on Chlamydia pneumoniae and Alzheimer disease, as well as with the work of Itzhaki et al. (Herpes simplex virus I), and Miklossy et al. (Borrelia species), this scenario may be more likely. Thus, in both systemic as well as brain infections of older and aged individuals, the triggering of systemic and/or brain inflammatory responses may initiate structural and functional change in the brain, resulting in early damage, such as amyloid generation/deposition, that may precede and/or promote more extensive neurodegeneration.
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