BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is the prevalent neurodegenerative disease of the elderly, in which patients experience global cognitive impairments which eventually devolve to complete dementia. Pathologically, AD is typified by amyloid plaques in the forebrain and mediotemporal lobe structures, and subsequent research has implicated aberrant amyloid metabolism as one of the many possible causal factors for AD. Several strategies targeting the putatively toxic amyloid-β (Aβ) peptide are being explored experimentally (Austin et al., 2003, Comery et al., 2005, Dodart et al., 2002, Janus et al., 2000, Kotilinek et al., 2002, Morgan et al., 2000, Schenk et al., 1999). These strategies include active and passive amyloid-related immunization, as well as inhibition of the secretase enzymes that metabolize the Amyloid Precursor Protein (APP) to Aβ like the β-site aspartyl cleaving enzyme (BACE1) (Hussain et al., 1999, Sinha et al., 1999, Vassar et al., 1999, Yan et al., 1999). Several lines of evidence support BACE1 inhibition as a promising target for AD therapy: BACE1 is the initial and rate-limiting enzyme involved in Aβ processing; the primary β-secretase in neurons, is upregulated in AD and transgenic human mutant APP mouse brain tissues; and overexpression of BACE1 in transgenic mice has been linked to accelerated amyloid pathology and neurodegeneration (Bodendorf et al., 2002, Cai et al., 2001, Fukumoto et al., 2002, Fukumoto et al., 2004, Mohajeri et al., 2004, Rockenstein et al., 2005).
Genetically modified animal models have helped to significantly advance the body of knowledge for AD. Several transgenic models for amyloid-driven neurodegeneration now exist, including the PDAPP, Tg2576, APP23 and TgCRND8 mouse lines, which replicate some neuropathological and cognitive features of AD (Chishti et al., 2001, Dodart et al., 1999, Games et al., 1995, Hsiao et al., 1996, Rockenstein et al., 2005, Sturchler-Pierrat et al., 1997). Following on the success of these earlier models, animals lacking the BACE1 gene have also been engineered to assess potential liabilities and benefits of BACE1 activity reductions. BACE1−/− animals in general are viable, fertile and some lines can perform well at young ages in some behavioral tests (Laird et al., 2005, Luo et al., 2001, Ohno et al., 2006, Ohno et al., 2004, Roberds et al., 2001). However, other lines have notable anxiety phenotypes and are impaired with age in cognitive task performance, and are associated with other deleterious phenotypes like early death and reduced size (Dominguez et al., 2005, Harrison et al., 2003, Laird et al., 2005, Luo et al., 2001, Ohno et al., 2004, Roberds et al., 2001).
However, as AD is a neurodegenerative condition of the elderly, it is important to understand the possible repercussions of BACE1 reduction in aged animals. In this report, the cognitive and sensorimotor phenotypes of BACE1−/− mice bred to the PDAPP transgenic model are presented. Cognitive phenotypes of BACE1−/−/PDAPP+ and BACE1−/−/PDAPP+ animals across ages were examined with a modified version of the classic Morris water maze, in which mice were tested for criterion-based performance on a series of spatial tasks (Chen et al., 2000, Morris et al., 1982). Aged animals were tested for locomotor activity in an unfamiliar arena, and for motor coordination using the rotorod. As BACE1 deletion has been previously shown to abolish neuronal Aβ production, the initial working hypothesis of this study was that BACE1 gene ablation would also presumably ameliorate the spatial memory deficits present in PDAPP animals.
Section snippets
Generation of transgenic mice
BACE1−/− mice were generated as described previously (Roberds et al., 2001). Animals heterozygous for the BACE1 gene deletion (BACE1−/+) were bred to animals homozygous for the PDAPP transgene (PDAPP+/+) described previously, that overexpress human mutant V717F APP under the control of the neuron-specific platelet-derived growth factor promoter (Games et al., 1995). All subsequent PDAPP mice described have one copy of the transgene and are simply called PDAPP+ mice. The progeny of this mating
Visual cued navigation
Animals were tested in the VCN paradigm prior to serial spatial memory testing to ensure that animals were competent to swim and otherwise perform the rudiments of the water maze task. By Day 3 of VCN, animals of all genotypes and ages tested had similar performance levels, swimming to the visible platform in 10–20 s (data not shown). There were however, genotypic differences in average VCN performance on Day 1 (VCN D1) (Table 3). At 18 months BACE1−/−/PDAPP+ mice took longer to navigate to the
Discussion
When tested in a serial spatial memory paradigm BACE1−/−/PDAPP− animals had a pattern of spatial deficits that was distinct but also milder than that of PDAPP mice: moderate but lifelong deficits in learning rate and memory capacity, an age-related perseverative impairment, but intact spatial memory acquisition. Contrary to the initial hypothesis that BACE1 gene deletion would rescue PDAPP mouse memory deficits, BACE1−/−/PDAPP+ mice were severely impaired in all measures, performing like aged
Disclosure
Authors Dione Kobayashi, Michelle Zeller, Tracy Cole, Manuel Buttini, Lisa McConlogue, Sukanto Sinha, Stephen Freedman, Karen S. Chen are all current or former employees of Elan Pharmaceuticals, a for-profit company engaged in developing neurological disease therapies. Individual authors may own financial shares in Elan, but are not company Directors.
Acknowledgements
Thanks to Henry Grajeda, Clarissa Lew and Marla Piercy for technical assistance, Darrin Despain, Bridget Mahoney, Lilly Chen and Elizabeth Luddington for statistical expertise, and Dora Games, Russell Rydel, Dale Schenk and Peter Seubert for scientific discussion and commentary.
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