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. 2012 Sep;29(13):2342-51.
doi: 10.1089/neu.2012.2449. Epub 2012 Jul 2.

Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury

Fengshan Yu  1 , Yumin Zhang, De-Maw Chuang
Affiliations

Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury

Fengshan Yu et al. J Neurotrauma. 2012 Sep.

Abstract

Traumatic brain injury (TBI) leads to both acute injury and long-term neurodegeneration, and is a major risk factor for developing Alzheimer's disease (AD). Beta amyloid (Aβ) peptide deposits in the brain are one of the pathological hallmarks of AD. Aβ levels increase after TBI in animal models and in patients with head trauma, and reducing Aβ levels after TBI has beneficial effects. Lithium is known to be neuroprotective in various models of neurodegenerative disease, and can reduce Aβ generation by modulating glycogen synthase kinase-3 (GSK-3) activity. In this study we explored whether lithium would reduce Aβ load after TBI, and improve learning and memory in a mouse TBI model. Lithium chloride (1.5 mEq/kg, IP) was administered 15 min after TBI, and once daily thereafter for up to 3 weeks. At 3 days after injury, lithium attenuated TBI-induced Aβ load increases, amyloid precursor protein (APP) accumulation, and β-APP-cleaving enzyme-1 (BACE1) overexpression in the corpus callosum and hippocampus. Increased Tau protein phosphorylation in the thalamus was also attenuated after lithium treatment following TBI at the same time point. Notably, lithium treatment significantly improved spatial learning and memory in the Y-maze test conducted 10 days after TBI, and in the Morris water maze test performed 17-20 days post-TBI, in association with increased hippocampal preservation. Thus post-insult treatment with lithium appears to alleviate the TBI-induced Aβ load and consequently improves spatial memory. Our findings suggest that lithium is a potentially useful agent for managing memory impairments after TBI or other head trauma.

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Figures

FIG. 1.
FIG. 1.
Lithium reduces beta amyloid (Aβ) levels in the hippocampus 3 days post-TBI. (A) Representative Western blots of Aβ peptide are shown here. Three days post-TBI, several bands of Aβ oligomers were detected using the 6E10 antibody. A 27-kDa Aβ oligomer band (arrow) increased after TBI, and this increase was suppressed by lithium treatment (n=5/group; ##p<0.01; *p<0.05). (B) ELISA was performed 3 days after TBI to evaluate changes in Aβ42 levels. Aβ42 levels increased in the hippocampus after TBI, and this increase was attenuated by lithium treatment (n=12/group; ##p<0.01; *p<0.05). (C, D, and E) Representative microphotographs of Aβ staining with the 4G8 antibody in the corpus callosum 3 days after TBI are shown here. (F) The area of Aβ staining is indicated by an arrow in the H&E micrograph. (C) No Aβ-positive signal was found in the corpus callosum of the sham-injured animals. (D) Three days post-injury, a robust increase in Aβ accumulation in axonal bulbs was seen in the corpus callosum in the TBI model group. (E) Aβ accumulation was reduced in this area following lithium treatment. (G) Quantitative data showed a significant reduction in the area fraction of 4G8-positive staining in the lithium-treated group compared to the TBI group in the corpus callosum (n=6/group; **p<0.01; scale bar=50 μm). Nuclei were stained with DAPI as shown with blue fluorescence. Data are represented as mean±SEM. Levels of β-actin were used as loading control (H&E, hematoxylin and eosin; TBI, traumatic brain injury; SEM, standard error of the mean; ELISA, enzyme-linked immunosorbent assay; DAPI, 4,6-diamino-2-phenylindole).
FIG. 2.
FIG. 2.
Lithium reduces amyloid precursor protein (APP) accumulation in the corpus callosum and hippocampus 3 days post-TBI. Representative microphotographs of APP staining in the corpus callosum (B–D) and hippocampus (F–H) 3 days after injury are shown. Areas of APP staining are indicated by arrows in H&E micrographs (A and E). No APP-positive signal was found in the corpus callosum or hippocampus of the sham-injured animals (B and F). Three days post-TBI, enlarged axonal bulbs were dramatically increased in both areas in the TBI model group (C and G), and this was suppressed by lithium treatment (D and H). The inserts in photomicrographs C, D, G, and H are higher-magnification photographs of the arrow-pointed boxes. Quantitative data showed a significant reduction in the area fraction of APP accumulation in the lithium-treated group compared to the TBI model group for both the corpus callosum and hippocampus (I and J, respectively; n=6/group; *p<0.05; scale bar=50 μm). Nuclei were stained with DAPI as shown with blue fluorescence. Data are represented as mean±standard error of the mean (TBI, traumatic brain injury; DAPI, 4,6-diamino-2-phenylindole).
FIG. 3.
FIG. 3.
Lithium blocks TBI-induced BACE1 increases 3 days post-TBI. Representative Western blots showing that lithium blocked TBI-induced BACE1 increases 3 days after TBI. BACE1 was visualized as a band of around 70 kDa, and its levels were markedly increased in the ipsilateral hippocampus in the TBI model group compared with the sham-injured group (n=5/group; ##p<0.01), and this increase was completely blocked by lithium treatment (n=5/group; **p<0.01). Data are represented as mean±standard error of the mean. Levels of β-actin were used as loading control (TBI, traumatic brain injury; BACE1, β-APP-cleaving enzyme-1).
FIG. 4.
FIG. 4.
Lithium reduces Tau phosphorylation in the thalamus after TBI. Representative microphotographs of phospho-Tau (p-Tau) staining (A–C) in the thalamus 3 days after injury are shown. The area of p-Tau staining is indicated by an arrow in the H&E micrograph (E). No p-Tau-positive signal was detected in the thalamus of the sham-injured animals (A). A robust increase in p-Tau-positive cells was observed in the thalamus 3 days after TBI (B), which was significantly suppressed by lithium treatment (C). Quantitative data showing that lithium reduced the number of TBI-induced p-Tau-positive cells compared with the TBI model group (D; n=5/group; **p<0.01; scale bar=50 μm). Nuclei were stained with DAPI as shown with blue fluorescence. Data are represented as mean±standard error of the mean (TBI, traumatic brain injury; DAPI, 4,6-diamino-2-phenylindole; H&E, hematoxylin and eosin).
FIG. 5.
FIG. 5.
Lithium improves spatial learning in the Morris water maze and Y-maze tests. The Morris water maze test was conducted 17–20 days after TBI. During the hidden platform training portion of the test, the TBI group took significantly more time to locate the platform, indicating a deficit in spatial learning (A; n=17/group; ###p<0.001). Lithium treatment significantly improved this learning deficit, especially on day 20 (n=17/group; **p<0.01), compared with the TBI group. In the probe trial of the Morris water maze test performed 20 days following injury, TBI model mice spent less time in the target quadrant than sham-injured mice (B; n=10/group; #p<0.05). Lithium treatment reversed this (n=10/group, *p<0.05). The average swim speed did not differ between groups (C). The Y-maze test was conducted 10 days post-TBI to evaluate spatial learning. Ten days after TBI, the TBI model group spent significantly less time than sham-injured mice in the novel arm versus the total time spent in all three arms (D; n=12/group; ##p<0.01). In contrast, lithium treatment significantly attenuated this decline in the lithium-treated group (n=12/group; *p<0.05). Data are represented as mean±standard error of the mean (TBI, traumatic brain injury).
FIG. 6.
FIG. 6.
Lithium increases hippocampal tissue preservation after TBI. TBI caused massive hippocampal tissue loss 3 weeks after injury, and this tissue loss was reduced by lithium treatment (A). Quantified data showing that lithium significantly increased hippocampal tissue preservation (B; n=6; *p<0.05). Data are represented as mean±standard error of the mean (TBI, traumatic brain injury).
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