Research Models


Species: Mouse
Genes: BACE1
Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57B6/C3H
Availability: Unknown


Three lines of transgenic mice expressing different levels of human BACE were generated. Line 30 (BACE-L) expressed the lowest amount of BACE, followed by line 34 (BACE-M), and line 8 (BACE-H). These lines expressed human BACE at levels approximately 7-, 10-, and 20-fold over endogenous levels, respectively. Immunostaining showed increased BACE expression in neuronal cell bodies, axons and synaptic elements such as the mossy fiber terminals of the hippocampus, puncta within the granule cell layer of the cerebellum, and neuropil within the spinal cord. Monogenic BACE mice from all three lines showed no evidence of Aβ deposition (Lee et al., 2005).

In order to determine the impact of BACE overexpression on Aβ deposition, hBACE mice have been crossed with APP overexpressing mice, such as the Tg2576 model overexpressing APP with the Swedish mutation (Hsiao et al., 1996). BACE expression was comparable in the single BACE transgenic and the bigenic APPxBACE mice. At 14–16 months, APPxBACE-H and APPxBACE-M mice had decreased cortical deposition of Aβ relative to Tg2576 mice and almost no hippocampal Aβ deposits. This effect was dependent on BACE dose, as mice generated with the low-expressing line (APP-BACE-L) exhibited increased amyloid plaque formation within the cortex, although they had some diminution of hippocampal Aβ deposits. Although modest overexpression of BACE enhanced amyloid deposition, high BACE overexpression inhibited amyloid formation despite increased cleavage of APP (Lee et al., 2005).

Modification Details

A human BACE1 transgene is driven by the mouse prion protein (PrP) promoter.


  1. EB Lee and colleagues provide very interesting data indicating that high BACE overexpression paradoxically reduces Aβ levels and plaque pathology in Tg2576 transgenic mice harboring the APP Swedish mutation. They employ diverse methods to demonstrate that BACE overexpression reduces transport of mature and phosphorylated APP into axons. This publication underscores the importance of studying AD biology in neurons, especially their processes. Increasing evidence is placing the critical site of Aβ generation, and accumulation, within neurites and synapses. Disruption of the perforant path has previously been shown to reduce plaque pathology in synaptic terminal fields of the hippocampus. Aβ at synapses may even have a physiological role that as yet is poorly defined. A central but more controversial issue is how Aβ generation at synapses links to synaptic dysfunction and plaque formation. A topic not discussed in the paper is the growing literature on intraneuronal Aβ accumulation with AD pathogenesis. Indeed, the labs of Virginia Lee and John Trojanowski were pioneers in studies on intracellular Aβ. Their work raises the intriguing question of why the low BACE expressing APP mutant mice have reduced plaques in hippocampus but increased plaques in cortex. The authors speculate that differential effects of increased BACE in projection neurons with long axons compared to smaller interneurons with shorter axons may be involved. Despite the emphasis on axons and presynaptic compartments, one could also consider the potential involvement of dendrites and postsynaptic compartments, which are more difficult to study but also accumulate Aβ. Overall, this is exciting new work using rigorous analysis of APP/Aβ processing with elegant in vivo experiments that provide novel insights into the neurobiology of AD.

    View all comments by Gunnar Gouras
  2. I agree with Martin and Gouras that this paper deserves serious study since it is an ambitious attempt to explore whether cleavage of APP at different subcellular sites determines whether Abeta peptides are ultimately toxic to the neurons in which the are produced.

    The authors found that increased expression of beta secretase in mice has a paradoxical effect on Aβ levels and plaque development. High levels of beta secretase decrease Aβ levels and retard plaque formation, contrary to what might have been predicted. They propose that excessive beta secretase cleaves APP prematurely in the ER/Golgi regions of neurons, thereby reducing their translocation to distal segments where it is presumed that abeta peptides might be more toxic. While this is an interesting idea, I would look for deeper explanations.

    Other interesting effects are also described, such as a striking decrease in levels of phosphorylated C99, a product of beta cleavage, while non-phosphorylated C99 and other amino terminal fragments of APP accumulate inside cells. This makes one wonder whether high levels of beta secretase, or the peptides they generate, have as yet unsuspected actions that might influence other metabolic pathways including kinase/phosphatase actions and the PS1/gamma secretase complex.

    View all comments by Vincent Marchesi

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Paper Citations

  1. . BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.
  2. . Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102. PubMed.

Other Citations

  1. Tg2576

Further Reading

No Available Further Reading