Acute brain injuries have been identified as a risk factor for developing Alzheimer's disease (AD). Because glutamate plays a pivotal role in these pathologies, we studied the influence of glutamate receptor activation on amyloid-␤ (A␤) production in primary cultures of cortical neurons. We found that sublethal NMDA receptor activation increased the production and secretion of A␤. This effect was preceded by an increased expression of neuronal Kunitz protease inhibitory domain (KPI) containing amyloid-␤ precursor protein (KPI-APP) followed by a shift from ␣-secretase to ␤-secretase-mediated APP processing. This shift is a result of the inhibition of the ␣-secretase candidate tumor necrosis factor-␣ converting enzyme (TACE) when associated with neuronal KPI-APPs. This KPI-APP/ TACE interaction was also present in AD brains. Thus, our findings reveal a cellular mechanism linking NMDA receptor activation to neuronal A␤ secretion. These results suggest that even mild deregulation of the glutamatergic neurotransmission may increase A␤ production and represent a causal risk factor for developing AD.

Traumatic brain injury (TBI) causes a wide spectrum of consequences, such as microglial activation, cerebral inflammation, and focal and diffuse brain injury, as well as functional impairment. In this study we aimed to investigate the effects of acute treatment with minocycline as an inhibitor of microglial activation on cerebral focal and diffuse lesions, and on the spontaneous locomotor activity following TBI. The weight-drop model was used to induce TBI in mice. Microglial activation and diffuse axonal injury (DAI) were detected by immunohistochemistry using CD11b and ss-amyloid precursor protein (ss-APP) immunolabeling, respectively. Focal injury was determined by the measurement of the brain lesion volume. Horizontal and vertical locomotor activities were measured for up to 12 weeks post-injury by an automated actimeter. Minocycline or vehicle were administered three times post-insult, at 5 min (90 mg/kg i.p.), 3 h, and 9 h post-TBI (45 mg/kg i.p.). Minocycline treatment attenuated microglial activation by 59% and reduced brain lesion volume by 58%, yet it did not affect DAI at 24 h post-TBI. More interestingly, minocycline significantly decreased TBI-induced locomotor hyperactivity at 48 h post-TBI, and its effect lasted for up to 8 weeks. Taken together, the results indicate that microglial activation appears to play an important role in the development of TBI-induced focal injury and the subsequent locomotor hyperactivity, and its short-term inhibition provides long-lasting functional recovery after TBI. These findings emphasize the fact that minocycline could be a promising new therapeutic strategy for head-injured patients.

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