Mechanisms of Aging-associated, Immune Challenge-driven Cognitive Dysfunction
N. Tanaka, H. Anni, B. Metenko, and S. L. Patterson Temple Univ., Philadelphia, PA
Not all cognitive decline is gradual. Older individuals are more likely to experience an abrupt decline in mental function after events (e.g. infection, injury, or surgery) that trigger activation of the peripheral immune system. Even when this decline is temporary, it is associated with a greatly increased risk of progression to or acceleration of Alzheimer's disease or related dementias. Very little is known about the underlying mechanisms, but rodent models may provide some clues. Aging (24 month) F344xBN rats are generally healthy with no major physical or cognitive deficits. However, their brains respond to signals triggered by a peripheral immune challenge with an exaggerated inflammatory response, producing more pro-inflammatory cytokines like interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), and producing them longer, than those of younger (3 month) rats (Barrientos et al., 2009). This exaggerated elevation of IL-1β produces deficits in memory and synaptic plasticity that can be blocked by blocking IL-1 signaling in the brain (Chapman et al., 2010; Frank et al., 2010). The affected memory and plasticity processes are highly dependent on brain derived neurotrophic factor (BDNF), and we have demonstrated that the interaction of aging and infection significantly reduces specific plasticity-associated BDNF mRNA transcripts (Chapman et al., 2012), and BDNF protein/signaling (Cortese et al., 2011) in the hippocampus. To further investigate how age and an immune challenge can compromise the capacity for memory-related synaptic plasticity, we are now using multiplex gene expression analysis of whole hippocampal extracts and hippocampal subcellular fractions. Screening samples against a curated gene expression panel of over 700 genes, we have found that the combination of age and infection is associated with alterations in molecular networks functionally associated with BDNF. We have also found changes in expression of a number of microglial activation- and cytokine-related genes, and genes related to neurotransmitter synthesis and storage. By using functional and systems data from a novel, naturalistic model with clear links to dementia, we hope to gain insights into the processes associated with early-stage, specific failures of memory systems.
Supported by NIH Grant R01AG041944
Credits: None available.
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