Alzheimer's disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid beta-peptide (A beta), a 40-42-amino-acid fragment of the beta-amyloid precursor protein (APP). A primary pathogenic role for APP/A beta is suggested by missense mutations in APP that are tightly linked to autosomal dominant forms of AD. A major obstacle to elucidating and treating AD has been the lack of an animal model. Animals transgenic for APP have previously failed to show extensive AD-type neuropathology, but we now report the production of transgenic mice that express high levels of human mutant APP (with valine at residue 717 substituted by phenylalanine) and which progressively develop many of the pathological hallmarks of AD, including numerous extracellular thioflavin S-positive A beta deposits, neuritic plaques, synaptic loss, astrocytosis and microgliosis. These mice support a primary role for APP/A beta in the genesis of AD and could provide a preclinical model for testing therapeutic drugs.

Alzheimer's disease is characterized by the extracellular deposition of ␤-amyloid peptide (A␤) in cerebral plaques and evidence is accumulating that amyloid is neurotoxic. A␤ is derived from the ␤-amyloid precursor protein (APP). Proteolytic processing of APP by the enzyme, ␤-secretase, produces the N terminus of A␤, and releases a secreted ectodomain of APP (␤-s-APP). To develop animal models for measuring ␤-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 neuronspecific 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 ␤-s-APP in the brains of NSE-APP mice and enzyme-linked immunosorbent assay analyses showed production of A␤ 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 ␤-secretase cleavage necessary for generation of ␤-s-APP and A␤ is efficiently performed in neurons. In contrast, only little ␤-s-APP was detected in brain homogenates of GFAP-APP mice, indicating that astrocytes show very little ␤-secretase activity in vivo. This provides strong in vivo evidence that the major source of A␤ in brain is from neurons and not from astrocytes.The extracellular deposition of ␤-amyloid peptide (A␤) 1 in senile plaques is an early and invariant feature of Alzheimer's disease (AD). This 39 -43-amino acid peptide is the major component of plaques and is proteolytically processed from the ␤-amyloid precursor protein (APP) (1, 2). APP is expressed in all tissues, and the relative amount of A␤ processed from APP varies in different cell types in culture (3-5). The cellular source of A␤ deposited into plaques in the brain is unknown. Mutations in APP are responsible for some forms of familial AD, supporting the hypothesis that APP and A␤ are central to the disease process (6). Missense mutations immediately Nterminal to the A␤ region of APP 2 lead to a 5-10-fold enhancement of A␤ produced from APP in vitro, strongly supporting the role of A␤ in the development of AD in this family (7,8). Other families, with mutations at the 717 position of APP, have been shown to produce increased amounts of the more amyloidogenic 42-amino acid form of A␤ from APP (9). These findings suggest that factors governing the metabolic processing of APP play a direct pathogenic role in Alzheimer's disease.The majority of APP is cleaved in the middle of the A␤ region, releasing a secreted ectodomain containing the first 16 amino acids of A␤ (␣-s-APP). This processing, mediated by an unidentified enzymatic activity termed "␣-secretase" precludes A␤ formation (10). In an alternative pathway, cleavage between Met 671 and Asp 672 by a likewise unid...