Journal of Biological Chemistry
Volume 271, Issue 49, 6 December 1996, Pages 31407-31411
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Cell Biology and Metabolism
β-Secretase Processing of the β-Amyloid Precursor Protein in Transgenic Mice Is Efficient in Neurons but Inefficient in Astrocytes*

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Alzheimer's disease is characterized by the extracellular deposition of β-amyloid peptide (Aβ) in cerebral plaques and evidence is accumulating that amyloid is neurotoxic. Aβ is derived from the β-amyloid precursor protein (APP). Proteolytic processing of APP by the enzyme, β-secretase, produces the N terminus of Aβ, and releases a secreted ectodomain of APP (β-s-APP). To develop animal models for measuring β-secretase activity in specific brain cells in vivo, we have targeted the expression of the full-length human APP to either neurons or astrocytes in transgenic mice using the neuron- specific enolase (NSE) promoter or a modified glial fibrillary acidic protein (GFAP) gene, respectively. The APP cDNAs expressed were mutated (KM to NL at 670/671) to encode amino acid substitutions that enhance amyloidogenic processing in vitro. Western analyses revealed abundant production of β-s-APP in the brains of NSE-APP mice and enzyme-linked immunosorbent assay analyses showed production of Aβ in fetal primary mixed brain cultures and brain homogenates from these transgenic animals. Because the NSE promoter drives expression primarily in neurons, this provides in vivo evidence that the β-secretase cleavage necessary for generation of β-s-APP and Aβ is efficiently performed in neurons. In contrast, only little β-s-APP was detected in brain homogenates of GFAP-APP mice, indicating that astrocytes show very little β-secretase activity in vivo. This provides strong in vivo evidence that the major source of Aβ in brain is from neurons and not from astrocytes.

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This work was supported by National Institutes of Health Grant AG11385 (to L. Mucke) and by Athena Neurosciences, Inc. The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.