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The Journal of Neuroscience, May 1, 1998, 18(9):3213-3223

Stable Complexes Involving Acetylcholinesterase and Amyloid- Peptide Change the Biochemical Properties of the Enzyme and Increase the Neurotoxicity of Alzheimer's Fibrils

Alejandra Alvarez¹, Rodrigo Alarcón¹, Carlos Opazo¹, Eliseo O. Campos¹, Francisco José Muñoz¹, Frances H. Calderón¹, Federico Dajas², Mary K. Gentry³, Bhupendra P. Doctor³, Fernando G. De Mello⁴, and Nibaldo C. Inestrosa¹

¹ Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile, ² División de Neuroquímica, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay, ³ Division of Biochemistry, Walter Reed Army Institute of Research, Washington, DC, 20307-5100, and ⁴ Instituto de Biofisica, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid- peptide (A) during its assembly into filaments, in agreement with its colocalization with the A deposits of Alzheimer's brain. The association of the enzyme with nascent A aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the A aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of A fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

Key words: AChE; A-amyloid fibrils; AChE-A-amyloid fibril complexes; amyloid formation; Alzheimer's disease; neurotoxicity

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Copyright © 1998 Society for Neuroscience  0270-6474/98/1893213-11$05.00/0

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