Amyloid-β (Aβ) peptides, found in Alzheimer's disease brain, accumulate rapidly after traumatic brain injury (TBI) in both humans and animals. Here we show that blocking either β-or γ-secretase, enzymes required for production of Aβ from amyloid precursor protein (APP), can ameliorate motor and cognitive deficits and reduce cell loss after experimental TBI in mice. Thus, APP secretases are promising targets for treatment of TBI.TBI is the leading cause of mortality and disability among young individuals in developed countries, and globally the incidence of TBI is rising sharply 1 . TBI is a disease process, with an initial injury that induces biochemical and cellular changes that contribute to continuing neuronal damage and death over time. This continuing damage is known as secondary injury, and multiple apoptotic and inflammatory pathways are activated as part of this process (for reviews, see refs. 2,3 ). TBI is a major risk factor for the development of Alzheimer's disease 4,5 , and post-mortem studies show that 30% of TBI fatalities have Aβ deposits 6,7 . Remarkably, these deposits may occur less than 1 d after injury 8 . Not only does Aβ accumulate after TBI 9,10 , but also do the necessary APP enzymes responsible for Aβ production: β-APPcleaving enzyme-1 (BACE1) and presenilin-1, a γ-secretase complex protein [11][12][13][14] . Although the role of the APP secretases in secondary injury is unknown, multiple lines of evidence show that Aβ can cause cell death, activate inflammatory pathways [15][16][17][18] and prime proapoptotic pathways for activation by other insults 19 . The APP secretases may also be directly involved in secondary injury, as over-expressed BACE1 alone has been shown to cause neuronal cell loss in the absence of Aβ accumulation 20 . These facts make the APP secretases a potential therapeutic target for TBI.In our initial experiments, we characterized the TBI-induced protein changes in a nontransgenic mouse. We performed TBI by controlled cortical impact (CCI) of the left parietal cortex. This model induces both necrotic and apoptotic cell death, causing brain lesion and the development of behavioral deficits 21 . It has recently been reported that interstitial fluid Aβ concentrations correlate with neurological function in the injured human brain, with Aβ accumulating as neurological function improved in the days after trauma 22 . Exposure to experimental TBI resulted in accumulation of endogenous mouse Aβ x-40 peptide in the ipsilateral cortex within 1 d (Fig. 1a). Aβ levels increased by almost 120% at 3 d after injury before normalizing by 7 d (Fig. 1a) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptBace1 and presenilin-1 (Fig. 1b), as has been previously reported in other animal models and humans 9-14 . Soluble APP-α, which is purported to be neuroprotective 23 , was also increased after injury. Functionally, this model of TBI causes deficits in fine motor coordination (beam walk test, Supplementary Fig. 1a online) in the absence of gross motor def...
Abstract. To identify genes regulated during skeletal muscle differentiation, we have infected mouse C2C12 myoblasts with retroviral gene trap vectors, containing a promoterless marker gene with a 5' splice acceptor signal. Integration of the vector adjacent to an actively transcribed gene places the marker under the transcriptional control of the endogenous gene, while the adjacent vector sequences facilitate cloning. The vector insertionally mutates the trapped locus and may also form fusion proteins with the endogenous gene product. We have screened several hundred clones, each containing a trapping vector integrated into a different endogenous gene. In agreement with previous estimates based on hybridization kinetics, we find that a large proportion of all genes expressed in myoblasts are regulated during differentiation. Many of these genes undergo unique temporal patterns of activation or repression during cell growth and myotube formation, and some show specific patterns of subcellular localization. The first gene we have identified with this strategy is the lysosomal cysteine protease cathepsin B. Expression from the trapped allele is upregulated during early myoblast fusion and downregulated in myotubes. A direct role for cathepsin B in myoblast growth and fusion is suggested by the observation that the trapped cells deficient in cathepsin B activity have an unusual morphology and reduced survival in low-serum media and undergo differentiation with impaired cellular fusion. The phenotype is reproduced by antisense cathepsin B expression in parental C2C12 myoblasts. The cellular phenotype is similar to that observed in cultured myoblasts from patients with I cell disease, in which there is diminished accumulation of lysosomal enzymes. This suggests that a specific deficiency of cathepsin B could contribute to the myopathic component of this illness.T HE expression of a myogenic basic helix-100p-helix (bHLH) 1 transcription factor of the MyoD family is sufficient to convert a variety of cultured cells into skeletal muscle (for review see Mtinsterberg and Lassar, 1994), This initial switch is followed by an irreversible cascade of gene activation and repression events underlying the morphological differentiation. Earlier studies have analyzed global changes in sequence complexity and frequency distribution of messenger RNAs during muscle differentiation in vitro using DNA-RNA hybridization ki-*Dr. Harold Weintraub died on 28 March 1995.
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