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A4633 - Influenza A-Induced Pneumonia Accelerates Aging Related Cognitive Decline in Mouse Models
Author Block: F. J. Gonzalez1, A. C. Mc Quattie-Pimentel1, J. Yuan-Shih Hu1, C. Chen1, S. Watanabe1, D. Bowdish2, A. Misharin1, K. M. Ridge1, G. Budinger1; 1Respiratory and critical Care, Division of Pulmonary and Critical Care Medicine Northwestern University, Chicago, IL, United States, 2Pathology and Molecular Medicine, Research McMaster University, MDCL 4020, Hamilton, ON, Canada.
Rationale: The decline of cognitive function during aging is one of the most profound and debilitating
limitations to health-span in elderly. To understand the mechanisms that underlie the age-related
decline in cognition, most investigators have studied aged animals who have spent their lives shielded
from environmental stress. Pneumonia represents a common and serious form of environmental stress
that disproportionately affects older individuals. Elderly are at increased risk for bacterial and viral
pneumonias, and suffer from a higher morbidity, mortality and number of complications when
compared to younger individuals. There is a growing clinical and experimental evidence that viral and
bacterial pneumonias lead to long-lasting declines in cognitive function. These findings suggest the
presence of non-cell autonomous mechanisms linking pneumonia with cognitive decline.
Hypothesis: Age-related changes act synergistically with pneumonia to precipitate cognitive dysfunction
in cell non-autonomous manner via activation of microglia.
Methods: Young (2mo) and old (18 mo) C57Bl/6 mice intratracheally with a sublethal dose of influenza A
virus (PR8). Cognitive and motor performance was assessed pre-infection, 2 weeks after the infection
and 12 weeks after the infection using the panel of cognitive and behavioral tests. Transcriptional
profiling of the frontal cortex and FACSorted microglia was performed via RNA-seq.
Results: Aged mice performed worse in cognitive (open field and novel object recognition test) and
motor function tests (the rotarod and grip strength) than younger animals and that influenza A
pneumonia had more pronounced effect on older than on younger mice: while young mice
demonstrated almost complete recovery, the cognitive deficit persisted in older mice. Transcriptional
profiling of the frontal cortex revealed that genes associated with axonogenesis, synapse formation,
learning and memory were downregulated specifically in aged flu-treated mice. Transcriptional profiling
of microglia revealed upregulation of the genes associated with unfolded protein response and response
to proteostatic stress (Atf3, Dnajb1, Hsp90ab1, Hspa8), in young, but not in old mice, indicating
disruption of this adaptive mechanism in aged microglia.
Conclusions: Our data demonstrate that aged mice are more susceptible to pneumonia-associated
cognitive decline and indicate the role of cell-autonomous (aging-associated changes in microglia and
cortex) and non-cell autonomous (lung injury) factors in this process.