Modification: BACE1: Transgenic
Disease Relevance: Alzheimer's Disease
Strain Name: N/A
Genetic Background: C57B6/C3H
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).
Transgene of human BACE driven by the prion protein (PrP) promoter.
- Lee EB, Zhang B, Liu K, Greenbaum EA, Doms RW, Trojanowski JQ, Lee VM. 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.
- Hsiao K, Chapman P, Nilsen S, Eckman C, Harigaya Y, Younkin S, Yang F, Cole G. Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice. Science. 1996 Oct 4;274(5284):99-102. PubMed.
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