Role of neuroinflammation in neurodegeneration: new insights

Abstract

Previously, the contribution of peripheral infection to cognitive decline was largely overlooked however, the past 15 years have established a key role for infectious pathogens in the progression of age-related neurodegeneration. It is now accepted that the immune privilege of the brain is not absolute, and that cells of the central nervous system are sensitive to both the inflammatory events occurring in the periphery and to the infiltration of peripheral immune cells. This is particularly relevant for the progression of Alzheimer's disease, in which it has been demonstrated that patients are more vulnerable to infection-related cognitive changes. This can occur from typical infectious challenges such as respiratory tract infections, although a number of specific viral, bacterial, and fungal pathogens have also been associated with the development of the disease. To date, it is not clear whether these microorganisms are directly related to Alzheimer's disease progression or if they are opportune pathogens that easily colonize those with dementia and exacerbate the ongoing inflammation observed in these individuals. This review will discuss the impact of each of these challenges, and examine the changes known to occur with age in the peripheral immune system, which may contribute to the age-related vulnerability to infection-induced cognitive decline.

Keywords: Aging; Alzheimer’s disease; Amyloid-β; Infection; Neuroinflammation; T cells.

Fig. 1

The impact of infection on Alzheimer’s disease pathology. Healthy aging is accompanied by increased blood-brain barrier (BBB) permeability and an elevation in baseline inflammation however, Alzheimer’s disease (AD) is characterized by a significant increase in microglia activation, amyloid β (Aβ) deposition, BBB disruption and neuronal loss, far beyond that observed in non-demented, age-matched controls. It is established that microglia produce a range of cytokines in response to the growing presence of Aβ, however, with the increased number of T cells in the AD brain that have the capacity to interact with microglia, this can lead to elevated cytokine production. In addition, pathogens have been found in the AD brain, indeed many species were in close association with Aβ plaques. The presence of these microorganisms can exacerbate the ongoing neuroinflammation, thus negatively affecting nearby neuronal and glial cells leading to neurodegeneration. The situation is further confounded by inflammatory events occurring in the periphery, such as respiratory infection. This can result in increased immune cells and cytokines in circulation, which would have little influence on the healthy CNS, but the inflamed AD brain cannot efficiently handle this extra challenge. As the innate and adaptive immune cells of AD patients have altered reactivity, together they have the potential to further affect the BBB and exacerbate inflammatory changes within the CNS. This is an original figure, which was designed for this manuscript