Research Models


Species: Mouse
Genes: BACE1
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.

Phenotype Characterization

When visualized, these models will distributed over a 18 month timeline demarcated at the following intervals: 1mo, 3mo, 6mo, 9mo, 12mo, 15mo, 18mo+.


  • Plaques
  • Tangles

No Data

  • 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.

Neuronal Loss



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.

Synaptic Loss


Changes in LTP/LTD


Cognitive Impairment

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.


  1. This study, executed by Dr. Bettina Platt's laboratory, is an important step toward understanding the role of human BACE1 in Alzheimer’s disease. It is an elegant study that provides a better understanding of the physiological role of human BACE1. In fact, our laboratory demonstrated that BACE reduction resulted in a significant decrease of soluble Aβ-oligomers, preventing the development of wild-type human tau pathology and restoring cognition (Chabrier et al., 2012). Therefore, it would be of high interest to consider BACE1 as a potential target for therapeutic intervention.

    However, we need to interpret carefully the results obtained from this study.  PLB4 mice present both endogenous and human BACE1.  Therefore, it is possible that these mice produce more Aβ because they have more BACE1 activity; then the results of this study would not be specific to human BACE1.  A good strategy to resolve this issue is to cross hBACE1 mice with BACE knockout mice.

    Furthermore, BACE1 has many putative functions and substrates involved in cognitive function. Therefore, this model would be useful to determine the role of BACE1 in cognitive impairments.  Obviously, Aβ is a key molecular factor that might mediate BACE1 cognitive deficits, however, BACE1 also regulates cAMP/PKA signaling and controls voltage-gated sodium channels and serotonergic transmission.

    New findings reveal that BACE1 activity increases early in AD pathogenesis and it is elevated in patients with mild cognitive impairment. BACE1 appears to be an important factor for MCI patients to convert to AD (Cheng et al., 2014; Jiang et al., 2011; Zetterberg et al., 2008).  Therefore, this novel model will provide a great opportunity to better understand this phenomenon.


    . Soluble aβ promotes wild-type tau pathology in vivo. J Neurosci. 2012 Nov 28;32(48):17345-50. PubMed.

    . High activities of BACE1 in brains with mild cognitive impairment. Am J Pathol. 2014 Jan;184(1):141-7. PubMed.

    . Elevated CSF levels of TACE activity and soluble TNF receptors in subjects with mild cognitive impairment and patients with Alzheimer's disease. Mol Neurodegener. 2011;6:69. PubMed.

    . Elevated cerebrospinal fluid BACE1 activity in incipient Alzheimer disease. Arch Neurol. 2008 Aug;65(8):1102-7. PubMed.

    View all comments by Frank LaFerla
  2. I really like this paper. It shows that a mild overexpression of human BACE1 in mice can induce pathological changes similar to those seen in a human AD brain. It is amazing that the changes happen so early (behavioral and memory changes after a few months and pathology after about one year), although only endogenous APP is used. The paper is a great step toward the use of AD mouse models not overexpressing APP, and complements the recent Nat Neuroscience paper from Takaomi Saido’s lab (Saito et al., 2014). 

    The mouse model is a great basis for further studies. Given that BACE1 cleaves many different neuronal substrates, the authors should next cross their mouse with an APP knock-out mouse in order to figure out whether the behavioral/memory changes in their mouse are indeed only due to the increased amyloidogenic processing of APP or also due to increased cleavage of additional BACE1 substrates with brain functions. Additionally, it would be helpful if the mouse could be crossed with BACE1-deficient mice, such that only the overexpressed human BACE1 remains. Another point to study is the unexpected increase of C83. Is there really an increase in this a-secretase fragment or is this rather C89, i.e. the β-prime cleavage fragment, which results from the BACE1 cleavage site?

    As an additional point: the title "Knock-in of human BACE1…." is a bit oversimplified because it suggests that human BACE1 is knocked into the mouse BACE1 locus. In fact, their mouse mildlyover expresses human BACE1 that was knocked into a specific genetic locus, but not that of murine BACE1. Thus, the mouse has both the endogenous murine BACE1 plus the transgenically expressed human BACE1.  


    . Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.

    View all comments by Stefan Lichtenthaler
  3. We designed this mouse to express human BACE1 in neurons at relatively low levels as a more pathophysiologically relevant model for the human condition than mice overexpressing BACE or transgenes carrying familial AD mutations. PLB4 mice develop age-associated amyloidosis, inflammation, and behaviors indicative of deficits in learning and memory, all reminiscent of early stage AD. This model can be used to examine the biology of BACE1 in the brain, and to test if and how compounds that target β-secretase modulate the disease-related phenotypes. It would be interesting now to cross PLB4 with mice expressing human APP to investigate whether offspring develop end-stage amyloid pathology, such as plaques. We also observed a subtle metabolic phenotype in these mice that requires further investigation, as do the potential differences between male and female mice.

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Paper Citations

  1. . Knock-in of human BACE1 cleaves murine APP and reiterates Alzheimer-like phenotypes. J Neurosci. 2014 Aug 6;34(32):10710-28. PubMed.
  2. . Gene structure and organization of the human beta-secretase (BACE) promoter. FASEB J. 2004 Jun;18(9):1034-6. PubMed.
  3. . A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed.
  4. . 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.

Other Citations

  1. Bettina Platt

Further Reading