Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57BL/6J, for at least six generations
Availability: Available through Bettina Platt
This mouse model is useful for studying the biology of BACE1 and for investigating compounds that target β-secretase. The neuropathology and behavior of these mice indicate that even a subtle increase in human BACE1 expression, about twofold higher than endogenous, is enough to shift APP processing toward the amyloidogenic path, resulting in Aβ accumulation and age-associated behavioral changes consistent with cognitive impairment. These phenotypes occur in the absence of exogenous APP or familial mutations, suggesting that elevated BACE1 alone, and hence elevated β-secretase activity, is sufficient to trigger certain AD-related changes in these animals.
The PLB4 model, which takes its name from the senior investigator’s name (Platt, Bettina), was developed using a targeted knock-in strategy that directed transgene insertion to the HPRT locus, a permissive site on the X chromosome. This strategy bypasses potential confounds associated with random insertion, such as transgenic mutagenesis and the misregulation of essential genes. Although referred to as a knock-in, transgene expression in this model is regulated by the CaMKII-α promoter, not the endogenous Bace1 promoter and the murine Bace1 gene is intact. Transgene expression is largely restricted to forebrain neurons, as was confirmed by immunohistochemistry. Due to transgene insertion on the X chromosome, male knock-in mice are hemizygous for the transgene, whereas females can be either heterozygous or homozygous. In the original report, homozygous females were compared with hemizygous males because they had comparable human BACE1 levels due to X chromosome inactivation (Plucińska et al., 2014).
Transgenic human BACE1 was able to process endogenous murine APP in these mice as predicted, given the close homology of human and mouse BACE1 (Sambamurti et al., 2004). Effective cleavage was demonstrated by a decrease in full-length APP and an increase in CTF-β fragments. PLB4 mice accumulated high levels of oligomeric Aβ assemblies, including Aβ*56 and hexameric Aβ, which have been shown to be toxic in other models (Lesné et al., 2006; Billings et al., 2007).
Despite accumulating extracellular Aβ, mature amyloid plaques were very rarely seen in PLB4 mice, even at 12 months of age. The absence of plaques indicates that the behavioral deficits observed are not due to amyloid plaque deposition. Likewise, behavioral deficits are not due to tangles, as overt tau pathology is absent in PLB4 mice up to 12 months of age. Age-associated astrogliosis is observed, especially in the dentate gyrus, hippocampal CA1, and the piriform cortex.
The behavior of PLB4 mice has been extensively characterized. In general, their baseline motor functioning is normal, and they perform well on the Rotarod and Catwalk tests. However, their activity level decreases with age, and is significantly lower than wild-type animals at six and 12 months of age. The first real behavioral deficits were observed at three months of age, including delayed habituation to a novel environment, suggesting impaired formation of spatial representations. At slightly older ages, deficits became apparent in the Y maze, Morris water maze, and a semantic memory task, suggesting that BACE1 may affect spatial working memory, spatial learning, reference memory, and semantic-like memory. These impairments manifested around six months of age and appeared to be independent of the decreased motor activity and decreased anxiety also exhibited by PLB4 mice.
Although the animals breed well and are generally healthy, body weight diverges from wild-type animals with age. Male mice differ from wild-type at about six months, while females sustain normal weight until about nine months. The reason for the reduced body weight in PLB4 mice is not clear, but may be due to differences in feeding behavior, or perhaps underlying metabolic differences (Plucińska et al., 2014).
Available through Bettina Platt with MTA.
When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.
- Neuronal Loss
- Synaptic Loss
- Changes in LTP/LTD
Plaques virtually absent, minimal small sparse plaques. However, prominent extracellular Aβ staining surrounding neuronal cell bodies, including Aβ multimers (e.g. Aβ*56 and Aβ hexamers).
Preliminary analysis did not find abnormal phosphorylation or conformational changes in tau.
Increased GFAP-positive astrocytes at 12 months of age in the dentate gyrus, CA1 region of the hippocampus, and the piriform cortex. Gliosis is suspected to begin earlier than 12 months.
Changes in LTP/LTD
Impaired spatial representation in a habituation task by 3 months of age. By 6 months, impaired learning and memory by a variety of tasks including the Y-maze, Morris water maze, and a test of the social transmission of food preference. These effects appear to be distinct from reduced motor activity and reduced anxiety.
- Plucińska K, Crouch B, Koss D, Robinson L, Siebrecht M, Riedel G, Platt B. Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014 Aug 6;34(32):10710-28. PubMed.
- Sambamurti K, Kinsey R, Maloney B, Ge YW, Lahiri DK. Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J. 2004 Jun;18(9):1034-6. PubMed.
- Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed.
- Billings LM, Green KN, McGaugh JL, Laferla FM. Learning decreases A beta*56 and tau pathology and ameliorates behavioral decline in 3xTg-AD mice. J Neurosci. 2007 Jan 24;27(4):751-61. PubMed.