Chronic inflammation in brain tissue is a feature of neurodegenerative conditions, including those characterized by aggregation of misfolded proteins. This includes the synucleopathies, such as Parkinson's disease, in which which α-synuclein misfolds to produce toxicity, spreading through the brain to cause dysfunction and cell death. As researchers note here, this is accelerated by the presence of inflammatory signaling.
Age is the main risk factor for neurodegenerative disorders with dementia and movement dysfunction including Alzheimer's Disease (AD), Dementia with Lewy bodies (DLB), and Parkinson's Disease (PD). While in AD, amyloid beta (Aβ) and tau play a central role, in DLB and PD, ɑ-synuclein (ɑ-syn) is a key mediator. However, ɑ-syn has been shown to accumulate in the brain during aging and in AD and in DLB, Aβ, and tau are also found in conjunction with ɑ-syn in selected brain regions.
Under physiological conditions ɑ-syn is an intracellular protein that might play a role in neuroplasticity, however during aging and under pathological conditions ɑ-syn aggregates can be released to the extracellular space leading to cell to cell propagation spreading and seeding of small aggregates into preformed protofibrils (pff) and fibrils in neighboring neuronal and non-neuronal cells. Recent evidence has shown that the intrinsic structure of ɑ-syn fibrils dictates the characteristic of the synucleinopathies and for instance inoculation of selected ɑ-syn pff into the CNS can reproduce several aspects of the pathology of DLB/PD in wild type animals models.
Although protein aggregation and spreading have been extensively studied, less is known about the contribution of aging. One possibility by which aging might lead to neurodegeneration is dysregulation in immune cell function. This might be in part mediated by extracellular ɑ-syn propagating to glial cells. For example, it has been shown that ɑ-syn can activate innate immune responses via Toll like receptors.
In this study we evaluated the role of aging in neurodegeneration in the ɑ-syn pff model. We found that inoculation of ɑ-syn pff in aged mice resulted in greater spreading and deficits compared to young mice, with ɑ-syn pff-inducing gene networks in young mice that overlapped with genes differentially expressed in aged mice. We propose that changes in inflammatory gene expression underly the increased susceptibility of aged mice to enhanced ɑ-syn induced pathology and might represent a new avenue for therapeutics.