Prolonged neurobehavioral impairments and progressive neurodegeneration following experimental brain injury: Implications for traumatic brain injury and Alzheimer's disease

Date of Completion

January 1996


Biology, Neuroscience|Health Sciences, Rehabilitation and Therapy|Health Sciences, Pathology




Two models of traumatic brain injury, lateral fluid-percussion and controlled cortical impact, were used to explore the long-term neurobehavioral and histopathological changes induced by experimental brain injury. Lateral fluid-percussion brain injury in the rat is a well-established brain injury model which produces clinically relevant changes including memory dysfunction and neuronal loss. Sprague-Dawley rats were examined for cognitive and neurologic motor changes up to one year after lateral fluid-percussion brain injury. Their brains were subsequently examined immunohistochemically for changes in amyloid precursor protein and $\beta$-amyloid peptide associated with Alzheimer's disease neuropathology. Transgenic mice expressing human amyloid precursor protein were subjected to controlled cortical impact injury, and their brains were examined for changes in amyloid precursor protein and $\beta$-amyloid peptide.^ Prolonged learning and neurologic motor impairment were observed up to one year after injury in the rat. Learning deficits in the Morris water maze were detected as early as one week after injury and persisted up to one year. During this time course, overall neurologic motor function appeared to recover. However, selective tests revealed persistent forelimb impairment up to one year after injury.^ No injury-induced deposits of $\beta$-amyloid peptide were identified in the brains of either rats or mice. However, both species showed widespread accumulation of amyloid precursor protein-immunoreactive material, indicative of axonal injury. In rats, amyloid precursor protein accumulation appeared within one hour after injury and continued to appear in certain brain regions up to one year, suggesting ongoing neurodegeneration. Injured mice showed a similar distribution of amyloid precursor protein accumulation, which was not influenced by expression of the human amyloid precursor protein transgene.^ These findings do not represent the development of an animal model of Alzheimer's disease, nor do they replicate Alzheimer's disease-like neuropathological alterations observed following some cases of human traumatic brain injury. However, the observation of prolonged neurobehavioral and neuropathological effects of experimental brain injury potentially introduces a wider window of opportunity for therapeutic intervention. Furthermore alterations in amyloid precursor protein immunohistochemistry suggest that these models may be useful in understanding normal and abnormal processing of amyloid proteins. ^