Gradual cognitive decline does develop with senescence. However, it has frequently been noted that cognitive declines in older individuals often occur precipitously, &that these drops are typically preceded by events (surgery, viral or bacterial infection, injury) that involve peripheral inflammation/innate immune cell activation. Importantly, even when there is recovery from such declines, their occurrence is a predisposing factor to the development of long-term dementia. The cause(s) of this type of aging-related cognitive decline are unknown, &the long-term goal is to understand the mechanisms involved &develop appropriate therapies. During the past grant period we validated an animal model of this process, developed a mechanistic set of hypotheses to account for this phenomenon, &provided preliminary evidence in support. Work conducted during the past grant period &the further work here proposed is directed at understanding this phenomenon &its causes, as well as the discovery of therapeutic interventions. The hypothesis that has been developed involves several steps: 1) Peripheral inflammatory events signal the brain. 2) Microglia in specific brain regions become activated as part of the cascade of events in the brain induced by the "I am sick/injured" signal from the periphery, &the microglia produce inflammatory mediators, such as interleukin-1 (IL-1). Thus, peripheral inflammation leads to neuroinflammation. 3) Inflammatory mediators, particularly IL-1, can interfere with neural plasticity (e.g., long-term potentiation, LP) in regions such as the hippocampus, &therefore disrupt processes such as hippocampal long-term memory formation. IL-1 can do so directly &by interfering with other processes known to be critical for neural plasticity &memory formation. We have, &continue to test the hypothesis that large &prolonged elevations of IL-1 interfere with brain derived neurotrophic factor (BDNF) transcription &post-translational processing, &BDNF is well accepted as a critical mediator of synaptic plasticity &memory. 4) Aging primes or sensitizes microglia. This is the key assertion with regard to aging. During neurodegenerative disease microglia are overtly inflammatory in that their phenotype has shifted to ongoing production of inflammatory molecules. During pre-senescent aging, microglia show upregulated markers of activation, but they do not typically produce increased ongoing levels of inflammatory products such as IL-1. However, if stimulated they produce exaggerated quantities of inflammatory products, &do so for prolonged periods. 5) Thus, peripheral inflammation should lead to an exaggerated neuroinflammatory response in aging individuals, &we have demonstrated that this is the case. 6) The exaggerated amount &duration of the brain IL-1 increase in aging subjects during peripheral inflammation should interfere with cognitive processes such as memory for a prolonged period of time. Here these will all be tested. Here we explore the nature of microglia sensitization with age, its causes, and its cures. We also determine whether these cures prevent IL-1, BDNF, and memory deterioration.

Public Health Relevance

Gradual cognitive decline does develop with senescence. However, it has frequently been noted that cognitive declines in older individuals often occur precipitously, &that these drops are typically preceded by events (surgery, viral or bacterial infection, injury) that involve peripheral inflammation/innate immune cell activation. Importantly, even when there is recovery from such declines, their occurrence is a predisposing factor to the development of long-term dementia. The cause(s) of this type of aging-related cognitive decline are unknown, &the long-term goal is to understand the mechanisms involved &develop appropriate therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
2R01AG028271-06A1
Application #
8289902
Study Section
Neuroendocrinology, Neuroimmunology, Rhythms and Sleep Study Section (NNRS)
Program Officer
Mackiewicz, Miroslaw
Project Start
2006-04-01
Project End
2017-02-28
Budget Start
2012-03-15
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$417,285
Indirect Cost
$140,825
Name
University of Colorado at Boulder
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Barrientos, Ruth M; Thompson, Vanessa M; Arnold, T Hayes et al. (2015) The role of hepatic and splenic macrophages in E. coli-induced memory impairments in aged rats. Brain Behav Immun 43:60-7
Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T et al. (2012) Aging and infection reduce expression of specific brain-derived neurotrophic factor mRNAs in hippocampus. Neurobiol Aging 33:832.e1-14
Barrientos, Ruth M; Frank, Matthew G; Crysdale, Nicole Y et al. (2011) Little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes. J Neurosci 31:11578-86
Cortese, Giuseppe P; Barrientos, Ruth M; Maier, Steven F et al. (2011) Aging and a peripheral immune challenge interact to reduce mature brain-derived neurotrophic factor and activation of TrkB, PLCgamma1, and ERK in hippocampal synaptoneurosomes. J Neurosci 31:4274-9
Chapman, Timothy R; Barrientos, Ruth M; Ahrendsen, Jared T et al. (2010) Synaptic correlates of increased cognitive vulnerability with aging: peripheral immune challenge and aging interact to disrupt theta-burst late-phase long-term potentiation in hippocampal area CA1. J Neurosci 30:7598-603
Frank, Matthew G; Barrientos, Ruth M; Hein, Amy M et al. (2010) IL-1RA blocks E. coli-induced suppression of Arc and long-term memory in aged F344xBN F1 rats. Brain Behav Immun 24:254-62
Hein, Amy M; Stasko, Melissa R; Matousek, Sarah B et al. (2010) Sustained hippocampal IL-1beta overexpression impairs contextual and spatial memory in transgenic mice. Brain Behav Immun 24:243-53
Barrientos, Ruth M; Frank, Matthew G; Watkins, Linda R et al. (2010) Memory impairments in healthy aging: Role of aging-induced microglial sensitization. Aging Dis 1:212-231
Frank, Matthew G; Barrientos, Ruth M; Watkins, Linda R et al. (2010) Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo. J Neuroimmunol 226:181-4
Barrientos, Ruth M; Frank, Matthew G; Hein, Amy M et al. (2009) Time course of hippocampal IL-1 beta and memory consolidation impairments in aging rats following peripheral infection. Brain Behav Immun 23:46-54

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