BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Introduction
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia among the elderly population, but no treatments addressing the underlying cause of disease have been developed. One of the hallmarks of AD is extensive neuronal death in the brain, approaching 90% loss in certain regions such as entorhinal cortex and nucleus basalis (for review, see Morrison and Hof, 1997). Although the precise mechanisms of AD and related cell loss and memory deficits are not fully determined, data support the hypothesis that amyloid-β (Aβ) peptides trigger a pathologic cascade ultimately leading to neuron death and cognitive impairment in AD (Hardy and Selkoe, 2002, LaFerla and Oddo, 2005, Selkoe and Schenk, 2003, Sisodia and St George-Hyslop, 2002, Turner et al., 2003). Mutations in the genes for amyloid precursor protein (APP) and presenilins 1/2 (PS1/2) cause familial AD (FAD) and increase production of the 42-amino acid form of Aβ (Aβ42). Furthermore, Aβ kills neurons in culture (for review, see Yankner, 1996), and Aβ also appears neurotoxic in vivo. For example, when directly injected into the brains of aged primates, fibrillar Aβ causes neuron death around the injection site (Geula et al., 1998). However, the case for the role of Aβ in neuron death has been challenged because many APP transgenic mice that overproduce Aβ form amyloid plaques and develop memory deficits but do not lose significant numbers of neurons (Irizarry et al., 1997a, Irizarry et al., 1997b; for review, see McGowan et al., 2006). Recently, new APP/PS1 transgenic mouse lines developed by our group and others show considerable neuron loss in the hippocampus (Casas et al., 2004, Schmitz et al., 2004) or the cortex and subiculum (Oakley et al., 2006). These studies suggest that Aβ does kill neurons in vivo, although they cannot formally exclude the possibility that overexpression of APP and PS1 with multiple FAD mutations is the cause of neuron death in these mouse models.
β-Site APP-cleaving enzyme 1 (BACE1) has been identified as the β-secretase, the protease that initiates cleavage of APP to generate pathogenic Aβ peptides (Haniu et al., 2000, Hussain et al., 1999, Sinha et al., 1999, Vassar et al., 1999, Yan et al., 1999). As the rate-limiting enzyme for Aβ production, BACE1 is a prime therapeutic target for lowering cerebral Aβ levels in AD. Targeted deletion of the BACE1 gene (BACE1−/−) in mice abrogates the production of Aβ (Cai et al., 2001, Luo et al., 2001, Roberds et al., 2001). Moreover, APP transgenic mice with the BACE1 null genotype do not form amyloid plaques (Laird et al., 2005, Luo et al., 2003) and are prevented from developing Aβ-dependent memory deficits (Laird et al., 2005, Ohno et al., 2006, Ohno et al., 2004; for review, see Ohno, 2006). In the present study, we have used BACE1−/− mice to demonstrate that Aβ, rather than mutant APP or PS1 overexpression, is the cause of neuron loss in our APP/PS1 transgenic mouse line, 5XFAD (Oakley et al., 2006, Ohno et al., 2006). We determined that BACE1-deficient 5XFAD (BACE1−/−·5XFAD) mice do not have the amyloid plaques, astogliosis or memory deficits found in age-matched 5XFAD mice with wild-type BACE1 genes. Most importantly, neuron death in the cerebral cortex and subiculum was prevented in the BACE1−/−·5XFAD mice. To our knowledge, this is the first demonstration of genetic rescue of neuronal loss via ablation of BACE1, and consequently of Aβ, in an Alzheimer’s transgenic mouse model and provides strong evidence that Aβ ultimately kills neurons in vivo.
Section snippets
Animals
We used APP/PS1 doubly transgenic mice that co-express and co-inherit both human APP and PS1 transgenes with a total of five FAD mutations under transcriptional control of the neuron-specific mouse Thy-1 promoter [5XFAD mice, Tg6799 line (Oakley et al., 2006, Ohno et al., 2006)]. In 5XFAD mice, an APP transgene carrying triple FAD mutations [the Swedish mutation: K670N, M671L (Mullan et al., 1992); the Florida mutation: I716V (Eckman et al., 1997); the London mutation: V717I (Goate et al., 1991
Results
APP transgenic mouse models recapitulate several features of AD, such as amyloid pathology, synaptic dysfunction, and behavioral deficits, but there has been little demonstration of extensive neuronal loss in these models (Ashe, 2001, Dodart et al., 2002, German and Eisch, 2004, Irizarry et al., 1997a, Irizarry et al., 1997b, Janus and Westaway, 2001, Kobayashi and Chen, 2005, McGowan et al., 2006). We recently developed a novel APP/PS1 doubly transgenic mouse line [5XFAD mice, Tg6799 line (
Discussion
It is well established that Aβ kills neurons in culture (Pike et al., 1991, Roher et al., 1991, Yankner et al., 1990a, Yankner et al., 1989, Yankner et al., 1990b), but the link between Aβ and neuron loss in vivo has been equivocal. Cerebral injection of Aβ preparations into primates and rodents has produced variable effects, with some experiments demonstrating neurodegenerative changes (Frautschy et al., 1991, Geula et al., 1998, Kowall et al., 1991), while others yielding negative results (
Acknowledgments
This work was supported by National Institutes of Health grants R01 MH067251 (M.O.), R01 AG022560 (R.V.), P01 AG021184 (R.V. and R.B.) and R37 AG08796 (J.F.D).
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