Social and Behavioral Sciences Commons^™

Closed Head Injury In An Age-Related Alzheimer Mouse Model Leads To An Altered Neuroinflammatory Response And Persistent Cognitive Impairment, Scott J. Webster, Linda J. Van Eldik, D. Martin Watterson, Adam D. Bachstetter

Sanders-Brown Center on Aging Faculty Publications

Epidemiological studies have associated increased risk of Alzheimer's disease (AD)-related clinical symptoms with a medical history of head injury. Currently, little is known about pathophysiology mechanisms linked to this association. Persistent neuroinflammation is one outcome observed in patients after a single head injury. Neuroinflammation is also present early in relevant brain regions during AD pathology progression. In addition, previous mechanistic studies in animal models link neuroinflammation as a contributor to neuropathology and cognitive impairment in traumatic brain injury (TBI) or AD-related models. Therefore, we explored the potential interplay of neuroinflammatory responses in TBI and AD by analysis of the temporal …

Obesity And Diabetes Cause Cognitive Dysfunction In The Absence Of Accelerated Β-Amyloid Deposition In A Novel Murine Model Of Mixed Or Vascular Dementia, Dana M. Niedowicz, Valerie L. Reeves, Thomas L. Platt, Katharina Kohler, Tina L. Beckett, David K. Powell, Tiffany L. Lee, Travis R. Sexton, Eun Suk Song, Lawrence D. Brewer, Caitlin S. Latimer, Susan D. Kraner, Kara L. Larson, Sabire Özcan, Christopher M. Norris, Louis B. Hersh, Nada M. Porter, Donna M. Wilcock, Michael Paul Murphy

Sanders-Brown Center on Aging Faculty Publications

Mid-life obesity and type 2 diabetes mellitus (T2DM) confer a modest, increased risk for Alzheimer's disease (AD), though the underlying mechanisms are unknown. We have created a novel mouse model that recapitulates features of T2DM and AD by crossing morbidly obese and diabetic db/db mice with APP^ΔNL/ΔNLx PS1^P264L/P264L knock-in mice. These mice (db/AD) retain many features of the parental lines (e.g. extreme obesity, diabetes, and parenchymal deposition of β-amyloid (Aβ)). The combination of the two diseases led to additional pathologies-perhaps most striking of which was the presence of severe cerebrovascular pathology, including aneurysms and small …

Activation Of Matrix Metalloproteinases Following Anti-Aβ Immunotherapy; Implications For Microhemorrhage Occurrence, Donna M. Wilcock, Dave Morgan, Marcia N. Gordon, Tiffany L. Taylor, Lisa A. Ridnour, David A. Wink, Carol A. Colton

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Anti-Aβ immunotherapy is a promising approach to the prevention and treatment of Alzheimer's disease (AD) currently in clinical trials. There is extensive evidence, both in mice and humans that a significant adverse event is the occurrence of microhemorrhages. Also, vasogenic edema was reported in phase 2 of a passive immunization clinical trial. In order to overcome these vascular adverse effects it is critical that we understand the mechanism(s) by which they occur.

METHODS: We have examined the matrix metalloproteinase (MMP) protein degradation system in two previously published anti-Aβ immunotherapy studies. The first was a passive immunization study in which …

Cx3cl1 Reduces Neurotoxicity And Microglial Activation In A Rat Model Of Parkinson's Disease, Mibel M. Pabon, Adam D. Bachstetter, Charles E. Hudson, Carmelina Gemma, Paula C. Bickford

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Parkinson's disease is characterized by a progressive loss of dopaminergic neurons in the substantia nigra. The cause of the neurodegeneration is unknown. Neuroinflammation has been clearly shown in Parkinson's disease and may be involved in the progressive nature of the disease. Microglia are capable of producing neuronal damage through the production of bioactive molecules such as cytokines, as well as reactive oxygen species (ROS), and nitric oxide (NO). The inflammatory response in the brain is tightly regulated at multiple levels. One form of immune regulation occurs via neurons. Fractalkine (CX3CL1), produced by neurons, suppresses the activation of microglia. CX3CL1 …

Focal Cerebral Ischemia In The Tnfalpha-Transgenic Rat, L. Creed Pettigrew, Mark S. Kindy, Stephen W. Scheff, Joe E. Springer, Richard J. Kryscio, Yizhao Li, David S. Grass

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: To determine if chronic elevation of the inflammatory cytokine, tumor necrosis factor-alpha (TNFalpha), will affect infarct volume or cortical perfusion after focal cerebral ischemia.

METHODS: Transgenic (TNFalpha-Tg) rats overexpressing the murine TNFalpha gene in brain were prepared by injection of mouse DNA into rat oocytes. Brain levels of TNFalpha mRNA and protein were measured and compared between TNFalpha-Tg and non-transgenic (non-Tg) littermates. Mean infarct volume was calculated 24 hours or 7 days after one hour of reversible middle cerebral artery occlusion (MCAO). Cortical perfusion was monitored by laser-Doppler flowmetry (LDF) during MCAO. Cortical vascular density was quantified by stereology. …