BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer's disease

Abstract

Accumulation of cerebral amyloid-β (Aβ) has been implicated as a putative causal factor in the development of Alzheimer's disease (AD). Transgenic mice like the PDAPP line overexpress human mutant Amyloid Precursor Protein (hAPP) and recapitulate many features of AD, including amyloid neuropathology and cognitive deficits. Inhibition of the β-site aspartyl cleaving enzyme (BACE1) enzyme responsible for the first proteolytic cleavage that ultimately generates Aβ has been proposed as a strategy for AD therapy. To assess the theoretical repercussions of β-secretase activity reduction in an in vivo model of AD, BACE1^−/− mice bred to the PDAPP line were examined in a series of behavioral tasks. Although BACE1 gene ablation abolished hAβ accumulation, BACE1^−/− mice had unexpected sensorimotor impairments, spatial memory deficits, and displayed seizures, phenotypes which were severe on the PDAPP background. These results suggest that while excess Aβ is functionally pathological, BACE1-mediated processing of APP and other substrates play a role in “normal” learning, memory and sensorimotor processes.

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.