Cognitive decline, whether in the context of neurodegeneration and dementia or in the more colloquial setting of normal aging, is the result of multifactorial processes that operate decades before overt manifestations. While some of the genetic risk factors that contribute to these processes are understood, it is not clear why individuals decline at different rates and why some people experience more cognitive impairment simply as a result of getting older. Likewise, while neuroinflammation is known to play a significant role in neurodegeneration, the factors that precipitate such neuroinflammation are unclear, and it is unknown whether neuroinflammation begets neurodegeneration or vice versa. Finally, the role of peripheral inflammatory cell infiltration into the brain relative to the role of local neuroinflammation in driving or exacerbating neurodegeneration is poorly defined. A provocative hypothesis is that mild brain inflammation associated with numerous CNS and peripheral infections - infections that in themselves are common, acute, self-resolving, and subclinical - is an environmental trigger for the inexorable accumulation of neuronal injury and loss that culminates in memory impairment later in life. The specific hypothesis tested in this proposal is that infiltration of inflammatory monocytes into the brain during subclinical viral encephalitis in young adult mice accelerates neurodegeneration mediated by mutant tau expression. A well-characterized picornavirus model of acute encephalitis will be used to study infections that exhibit mild neuroinvasive properties and intranasal inoculation with influenza virus will be used to model peripheral infections that drive brain inflammation despite the absence of tropism to the CNS. In order to rapidly exploit current viral models and immune targeted mouse strains without extensive backcrossing and to alleviate issues surrounding MHC haplotype-dependent responses to infection, mice will be transduced via intracerebral injection of adeno-associated viruses encoding neuron-specific P301S mutant tau to drive neurodegeneration. These experiments are significant because they will uncover interactions between viral infection-induced brain inflammation and later life cognitive decline within the context of a genetic predisposition to such impairment. This may reveal novel therapeutic strategies that will ameliorate aging-related degradation of cognitive performance. The hypothesis that mild viral encephalitis in young adulthood accelerates tauopathy-associated neurodegeneration is conceptually innovative and the toolbox employed to test this hypothesis is technically innovative. Findings in this study will provide a sustained, powerful influence on the field by revealing the interactions of virus infection, microglial activation, inflammatory monocyte infiltration into the brain, and the evolution of neurodegeneration. This work will also support future efforts to determine whether multiple mild infections over the lifetime of an individual result in accumulation of neuroinflammatory insults and neural injury that culminates in age-related cognitive decline in the absence of genetic drivers.
The proposed research is relevant to public health because the discovery that mild brain inflammation in early adulthood triggered by acute infection with common environmental pathogens such as enteroviruses and influenza virus accelerates later life neurodegeneration and cognitive decline will reveal important and novel therapeutic targets to prevent such decline. Therefore, the proposed research is relevant to the mission of the NIH to provide fundamental knowledge that will enhance human health, lengthen life, and reduce illness and disability.
