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Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology
Published on: March 23, 2011
Susceptibility to acute cognitive dysfunction in aged mice is underpinned by reduced white matter integrity and
Dáire Healy1, Carol Murray1, Ciara McAdams1
1School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute & Trinity College Institute of Neuroscience, Trinity College Dublin, 152-160, Pearse St. Dublin 2, Dublin, Republic of Ireland.
Abstract:
Age is a significant but heterogeneous risk factor for acute neuropsychiatric disturbances such as delirium. Neuroinflammation increases with aging but the determinants of underlying risk for acute dysfunction upon systemic inflammation are not clear. We hypothesised that, with advancing age, mice would become progressively more vulnerable to acute cognitive dysfunction and that neuroinflammation and neuronal integrity might predict heterogeneity in such vulnerability. Here we show region-dependent differential expression of microglial transcripts, but a ubiquitously observed primed signature: chronic Clec7a expression and exaggerated Il1b responses to systemic bacterial LPS. Cognitive frailty (vulnerability to acute disruption under acute stressors LPS and double stranded RNA; poly I:C) was increased in aged animals but showed heterogeneity and was significantly correlated with reduced myelin density, synaptic loss and severity of white matter microgliosis. The data indicate that white matter disruption and neuroinflammation may be key substrates of the progressive but heterogeneous risk for delirium in aged individuals.
Insights
Aging increases vulnerability to acute cognitive dysfunction and delirium. White matter disruption and neuroinflammation predict this heterogeneous risk in older individuals.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Aging is a risk factor for neuropsychiatric disturbances like delirium.
- Neuroinflammation increases with age, but its role in acute dysfunction is unclear.
Purpose of the Study:
- To investigate age-related cognitive vulnerability and its link to neuroinflammation and neuronal integrity.
- To determine if neuroinflammation and neuronal integrity predict heterogeneous risk for acute cognitive dysfunction in aging.
Main Methods:
- Assessed cognitive frailty in aged mice exposed to lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C).
- Analyzed microglial gene expression, myelin density, synaptic loss, and white matter microgliosis.
Main Results:
- Aged mice showed increased cognitive frailty, with heterogeneous responses.
- Cognitive frailty correlated with reduced myelin density, synaptic loss, and white matter microgliosis.
- Aged brains exhibited primed microglial signatures, including chronic Clec7a expression and exaggerated IL-1beta responses to LPS.
Conclusions:
- White matter disruption and neuroinflammation are key factors in age-related cognitive dysfunction.
- These factors contribute to the progressive and heterogeneous risk of delirium in aging individuals.
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