Long-Term Effects of Traumatic Brain Injury in a Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting over 10% of the elderly population. Epidemiological evidence indicates that traumatic brain injury (TBI) is an important risk factor for developing AD later in life. However, which injury-induced processes that contribute to the disease onset remains unclear. The aim with the present study was to identify cellular processes that could link TBI to AD development, by investigating the chronic impact of two different injury models, controlled cortical impact (CCI) and midline fluid percussion injury (mFPI). The trauma was induced in 3-month-old tg-ArcSwe mice, carrying the Arctic mutation along with the Swedish mutation, and the influence of TBI on AD progression was analyzed at 12-and 24-weeks post-injury. The long-term effect of the TBI on memory deficiency, amyloid-␤ (A␤) pathology, neurodegeneration and inflammation was investigated by Morris water maze, PET imaging, immunohistochemistry, and biochemical analyses. Morris water maze analysis demonstrated that mice subjected to CCI or mFPI performed significantly worse than uninjured tg-ArcSwe mice, especially at the later time point. Moreover, the injured mice showed a late upregulation of reactive gliosis, which concurred with a more pronounced A␤ pathology, compared to uninjured AD mice. Our results suggest that the delayed glial activation following TBI may be an important link between the two diseases. However, further studies in both experimental models and human TBI patients will be required to fully elucidate the reasons why TBI increases the risk of neurodegeneration.

Mast Cell Activation, Neuroinflammation, and Tight Junction Protein Derangement in Acute Traumatic Brain Injury

“…The severity of a TBI pathogenesis may range from "mild" with a slight change in mental status or consciousness to "severe" with unconsciousness or amnesia after the brain injury. The acute and chronic effects of brain injuries vary significantly from person to person or in animal models of TBI [3,4]. Therefore, no two TBIs are the same with reference to the neuroimmune response and disease severity.…”

Traumatic brain injury in the presence of Aβ pathology affects neuronal survival, glial activation and autophagy

“…Astrogliosis is also characterized by the upregulation of intermediate filament proteins, and by the secretion of inflammatory mediators and growth factors. GFAP upregulation under pathological conditions has readily been observed in vivo 32 , 65 , 73 – 76 . We assessed GFAP protein expression in our model system and observed wide heterogeneity between cells, which is also commonly observed in vivo 77 .…”

SCF + G-CSF treatment in the chronic phase of severe TBI enhances axonal sprouting in the spinal cord and synaptic pruning in the hippocampus

“…A time-course study has revealed that about 60% of synapses are lost in hippocampal CA1 at 2 days post-injury; the synapses are increased to ~ 75% of pre-injury levels 60 days after TBI [ 63 ]. It has been shown that the synaptophysin expressing synapses in the hippocampus are significantly increased 24 weeks, but not 12 weeks, after TBI in a mouse model of Alzheimer’s disease [ 87 ], suggesting a delayed reaction of synaptogenesis after TBI. Our data demonstrate that both the excitatory (PSD-95 positive) and inhibitory (Gephyrin positive) synapses in both the contralateral and ipsilateral hippocampal CA1 are significantly increased at 12 months post-severe TBI as compared with the sham controls, indicating massive synaptogenesis occurring in the hippocampus during the chronic phase of severe TBI.…”