2012-2013 ARDRAF Project

*The Virginia Center on Aging which administers the Alzheimer’s and Related Diseases Research Award Fund for the Commonwealth of Virginia, provides seed money to researchers in Virginia to stimulate innovative research into biomedical and psychosocial aspects of dementia, including cell biology, caregiving, and animal modeling.

Excessive inflammation in aging population following brain injury impairs hippocampal neurogenesis and cognitive function: implications for Alzheimer’s disease

Dong Sun, MD, PhD

Virginia Commonwealth University

Studies have found that in the mammalian brain, new neurons are generated constantly in the hippocampus, a region responsible for learning and memory function. However, this neurogenic capacity is significantly decreased with aging. In addition, it appears that impaired neurogenesis in the hippocampus is a critical event in the development of AD. Both aging and traumatic brain injury (TBI) are leading risk factors for AD. The investigators recently found that TBI in an aging population induces heightened levels of neuroinflammatory responses, as well as decreased hippocampal neurogenesis and cognitive function. In this project they will explore how inflammation, the common pathological event found in AD and TBI, affects hippocampal neurogenesis and cognitive function. They will first assess the temporal profiles of inflammatory mediators in the hippocampus, cerebrospinal fluid, and serum in aged animals following TBI, and then examine the effect of combinational therapy by targeting neuroinflammation and promoting survival of new neurons on recovery of cognitive function.

(Dr. Sun may be contacted at 804/828-1318; dsun@vcu.edu)

REPORT:

Recent evidence suggests that impaired neurogenesis in the hippocampus is a critical event and may underlie cognitive deficits in AD. Aging and traumatic brain injury (TBI) are the leading risk factors in the development of AD. This
project tested the hypothesis that under neuropathological conditions, aging produces excessive inflammatory responses which impair hippocampal neurogenesis and cognitive function. In Aim 1, serum and brain tissue homogenates from young and aged rats at different time points following TBI were assayed to measure the expression levels of 24 cytokines/chemokines. Another group of animals was used to assess the level of hippocampal neurogenesis. In Aim 2,
minocycline and 7,8-DHF were used to target neuroinflammation and neurogenesis for improved cognitive function in animals following TBI. At the early time point, several pro-inflammatory cytokines/chemokines were expressed at high levels in both serum and brain, and the aged animals had a higher expression compared to their younger counterparts. At 3 days post-TBI when the inflammatory mediators were expressed at high levels, a decreased number of newly generated neurons were found in the injured aged brains as compared to age matched sham controls or their younger counterparts.  Short term minocycline treatment at the acute stage post-injury significantly attenuated TBI-induced inflammatory cell responses in the brain and the production of several pro-inflammatory cytokines particularly in the aged rats. The administration of 7,8-DHF at the same stage improved cognitive function. These studies suggest that targeting inflammation and neurogenesis may have therapeutic potential to improve cognitive recovery in aging populations.

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