Cerebral microemboli increase ß-amyloid protein deposition, MMP-9, and GFAP expression in the Alzheimer`s model of APP/PS1 double transgenic mice.

We investigated the effects of cerebral arterial microemboli on amyloid ß protein (Aß) deposition in the hippocampal region of amyloid precursor protein/presenilin 1 (APP/PS1) double transgenic mice and evaluated the role of cerebral arterial microemboli in Alzheimer's disease (AD) pathogenesis. The mice were divided into a wild-type sham surgery group (n = 15), a wild-type coupled with microemboli group (n =15), an APP/PS1 double transgenic sham surgery group (n =15) and an APP/PS1 double transgenic coupled with microemboli group (n =15). The microemboli mice were injected via the left internal carotid artery with 300 µL of a normal saline suspension containing 100 whole blood clot-derived microemboli (25-50 µm). The sham surgery mice were injected with equal volumes of saline. After the mouse model was established for 1, 2 or 4 weeks, the Aß1-42 deposition in the left hippocampal region and the matrix metalloproteinase-9 (MMP-9) and glial fibrillary acidic protein (GFAP) expression levels were determined through immunohistochemical staining. The Aß1-42 deposition level in the left hippocampi of transgenic microemboli group was significantly greater than in the transgenic sham group at week 1 and 2 (P<0.001) but not at week 4. No Aß1-42 deposition was detected in the wild-type groups. Only sporadic MMP-9- and GFAP-positive cells were observed in the wild-type sham group. Significantly more MMP-9- and GFAP-positive cells were detected in the transgenic groups (P<0.001), particularly in the transgenic microemboli group. An intragroup analysis of the time factor for the microemboli groups showed significantly more MMP-9- and GFAP-positive cells at week 1 than at week 2 or 4 (P<0.001). No difference was detected between time points in the sham groups. Cerebral microemboli increased Aß deposition in the hippocampal region of APP/PS1 double transgenic mice. MMP-9 and GFAP expression may play an important role in excess Aß deposition, which is caused by an imbalance between the protein's synthesis and removal.

A mechanistic investigation into non-infarcted brain injury induced by cerebral artery microemboli.

To establish a rat brain injury by non-infarction process model induced by cerebral artery microemboli which would be used to further explore the neural injury mechanisms of cerebral artery microemboli. Seventy-two Sprague-Dawley rats were randomly divided into the microemboli group and the sham group; 100 25-50 µm microemboli in 300 µl or the same amount of saline were injected into the left carotid artery, respectively. The severity of neuron damage was assessed 3 and 7 days after the operation, using haematoxylin-eosin (HE) staining and immunohistochemical staining for caspase-3. Immunohistochemical staining for CD11b and GFAP were used to quantitatively analyse hyperplasia and the activation of microglia and astrocytes. TNF-α expression was detected by using ELISA and the NF-κB expression was detected by employing Western blotting. The results of HE staining had shown that ischaemic infarct foci were not detected in either the microemboli group or sham group. Only a few apoptotic cells and a few cells with the positive expression of CD11b and GFAP were detected in the sham group. And compared with that of the sham group, the number of apoptotic cells and the positive expression of CD11b and GFAP in the microemboli group were significantly increased (P < 0.001). These parameters were also significantly increased 7 days after the operation compared to rats 3 days after surgery (P < 0.001). The expressions of TNF-α and NF-κB were significantly increased in the microemboli group (P < 0.001), and the increase of the expression of TNF-α and NF-κB on the 3 days was more significant compared to that of TNF-α and NF-κB on 7 days (P < 0.001). Injection of 25-50 µm microemboli at a dose of 100 microemboli in 300 µl into the carotid artery of rats did not result in cerebral infarction, but led to neuronal apoptosis, hyperplasia and activation of microglia and astrocytes. This leads us to conclude that TNF-α and NF-κB may play important roles in the pathogenesis of neuronal apoptosis induced by microemboli in the cerebral arteries.