BETA-SECRETASE PROCESSING OF THE BETA-AMYLOID PRECURSOR PROTEIN IN TRANSGENIC MICE IS EFFICIENT IN NEURONS BUT INEFFICIENT IN ASTROCYTES

Alzheimer's disease is characterized by the extracellular deposition o f beta-amyloid peptide (A beta) in cerebral plaques and evidence is ac cumulating that amyloid is neurotoxic, A beta is derived from the beta -amyloid precursor protein (APP). Proteolytic processing of APP by the enzyme, beta-secretase, produces the N terminus of A beta, and releas es a secreted ectodomain of APP (beta-s-APP), To develop animal models for measuring beta-secretase activity in specific brain cells in vivo , we have targeted the expression of the full-length human APP to eith er 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 amyloi dogenic processing in vitro, Western analyses revealed abundant produc tion of beta-s-APP in the brains of NSE-APP mice and enzyme-linked imm unosorbent assay analyses showed production of A beta in fetal primary mixed brain cultures and brain homogenates from these transgenic anim als, Because the NSE promoter drives expression primarily in neurons, this provides in vivo evidence that the beta-secretase cleavage necess ary for generation of beta-s-APP and A beta is efficiently performed i n neurons, In contrast, only little beta-s-APP was detected in brain h omogenates of GFAP-APP mice, indicating that astrocytes show very litt le beta-secretase activity in vivo. This provides strong in vivo evide nce that the major source of A beta in brain is from neurons and not f rom astrocytes.