Elsevier

Neuroscience

Volume 80, Issue 4, 11 August 1997, Pages 1255-1262
Neuroscience

Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury

https://doi.org/10.1016/S0306-4522(97)00007-9Get rights and content

Abstract

Previous studies suggest that traumatic brain injury is associated with increased risk factor for developing Alzheimer's disease. Furthermore, the extent of the risk seems to be most pronounced in Alzheimer's disease patients who carry the ϵ4 allele of apolipoprotein E, suggesting a connection between susceptibility to head trauma and the apolipoprotein E genotype. Apolipoprotein E-deficient mice provide a useful model for investigating the role of this lipoprotein in neuronal maintenance and repair. In the present study apolipoprotein E-deficient mice and a closed head injury experimental paradigm were used to examine the role of apolipoprotein E in brain susceptibility to head trauma and in neuronal repair. Apolipoprotein E-deficient mice were assessed up to 40 days after closed head injury for neurological and cognitive functions, as well as for histopathological changes in the hippocampus. A neurological severity score used for clinical assessment revealed more severe motor and behavioural deficits in the apolipoprotein E-deficient mice than in the controls, the impairment persisting for at least 40 days after injury. Performance in the Morris water maze, which tests spatial memory, showed a marked learning deficit of the apolipoprotein E-deficient mice when compared with injured controls, which was apparent for at least 40 days. At this time, histopathological examination revealed overt neuronal cell death bilaterally in the hippocampus of the injured apolipoprotein E-deficient mice.

The finding that apolipoprotein E-deficient mice exhibit an impaired ability to recover from closed head injury suggests that apolipoprotein E plays an important role in neuronal repair following injury and highlights the applicability of this mouse model to the study of the cellular and molecular mechanisms involved.

Section snippets

Induction of closed head injury

ApoE-knockout mice and control mice from the same parent litter were kindly provided by Dr J. L. Breslaw.[18]CHI was induced under ether anaesthesia, confirmed by testing corneal and pupillary reflexes, in four-month-old male apoE-deficient (n=18) and control (n=12) mice weighing 30–36 g. In brief, trauma was caused by a modified electric weight-drop device[2]that was allowed to free-fall until the silicone tip (diameter 3 mm) hit the exposed skull on the left cerebral hemisphere, ∼1–2 mm lateral

Clinical evaluation

The neurological status of the injured mice was evaluated by measuring NSS at different intervals following CHI. As can be seen (Fig. 1), the two groups displayed a similar NSS at 1 h, indicating similar severity of injury. They also showed parallel recovery during the first week following CHI, the NSS reaching a value of ∼12. However, there were marked differences between the two groups in the extent of their subsequent recovery. Whereas the control mice (n=12) gradually and persistently

Discussion

The results of the present study demonstrate that apoE-deficient mice show greater cognitive and neurological derangement than do control mice for up to at least 40 days following CHI. These disturbances were associated with more pronounced neuronal cell death in the hippocampus of the apoE-deficient mice. The paradigm of injury and the early (within 1 h of CHI) damage were essentially similar in the two groups of mice, as evidenced by the similar NSS at 1 h, suggesting that the increased

Conclusions

The present results show that apoE-deficient mice are highly susceptible to the sequalae of head trauma and suggest that the increased vulnerability is due to defects in apoE-dependent neuronal repair mechanisms. This model may replicate head trauma-related pathogenic processes and provide a useful tool for studying the synergistic effects of traumatic head injury and ApoE in the development of AD.

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