Acetylcholinesterase induces the expression of the -amyloid precursor protein in glia and activates glial cells in culture Rommy von Bernhardi, a,c, * Gigliola Ramı ´rez, a,c Giancarlo V. De Ferrari, b and Nibaldo C. Inestrosa b a Departamento de Neurologı ´a, Facultad de Medicina, Pontificia Universidad Cato ´lica de Chile, Santiago, Chile b Centro de Regulacio ´n Celulary Patologı ´a Dr. Joaquı ´n V. Luco, MIFAB, Facultad de Ciencias Biolo ´gicas, Pontificia Universidad Cato ´lica de Chile, Santiago, Chile c Facultad de Medicina, Universidad de los Andes, Santiago, Chile Received 6 February 2003; revised 20 May 2003; accepted 13 August 2003 Abstract Acetylcholinesterase (AChE) activities in CNS physiopathology are increasingly diverse and range from neuritogenesis, through synaptogenesis, to enhancement of amyloid fiber assembly. In Alzheimer’s disease, senile plaques and neurodegeneration specially affect regions enriched for cholinergic synapses. In this study we show an effect of AChE that could contribute to the increased deposition of A in certain regions. Affinity-purified AChE induced the expression of amyloid--precursor protein (-APP) in glial cells in a concentration- dependent manner up to 5 nM. In glia, AChE also increased inducible nitric oxide synthase (iNOS) assessed by immunocytochemistry and decreased reductive metabolism as evidence of cell activation. AChE could increase the expression of -APP in astrocytes and microglia as result of the activation of glial cells. As a whole, we found that AChE has additional effects that could result in an increased synthesis of A, both by increasing -APP expression of astrocytes and by further activating glial cells. © 2003 Elsevier Inc. All rights reserved. Keywords: Acetylcholinesterase; AChE inhibitors; -APP; Alzheimer’s disease; iNOS; Glia Introduction Senile plaques and neurofibrillary tangles, the principal neuropathological lesions of Alzheimer’s disease (AD), are abundant in regions enriched for cholinergic synapses (Geula and Mesulam, 1999; Mora ´n et al., 1993). Acetylcho- linesterase (AChE) associates to senile plaques (Wright et al., 1993), and we have reported that AChE has toxic effects both in neuron- and glial-like cell lines (Caldero ´n et al., 1998). However, the selective neurodegeneration of a few brain regions is not well understood. AChE may have a role in AD, as suggested by several lines of evidence: First, AChE increases A aggregation (Alvarez et al., 1997; 1998, De Ferrari et al., 2001); AChE promotes the generation of amyloid aggregates by acceler- ating the assembly of A peptide into A fibrils (Inestrosa et al., 1996), an effect also described by Bartoli et al. (2003). Recent studies in double transgenic mice over expressing human APP (Swedish mutation) and human AChE also support the notion that AChE accelerates A deposition. The double AChE-APP transgenic mice present more and bigger plaques than control animals and start to form amy- loid plaques much earlier than mice expressing only the APP transgenic (Rees et al., 2003). Second, cholinesterase inhibitors increase the secretion of nonamyloidogenic soluble derivatives of APP (Mori et al., 1995), while tacrine increased the production of amy- loidogenic fragments (Chong and Suh, 1996). Third, exper- imental lesion of the basal forebrain cholinergic system suggested that the loss of the cholinergic innervation affects APP expression (Lin et al., 1998), although it was found that * Corresponding author. Faculty of Medicine, Department of Neurol- ogy, Pontificia Universidad Cato ´lica de Chile, Av. Libertador Bernardo O’Higgins 340, Santiago, Chile. Fax: +56-2-632-1924. E-mail address: rvonb@med.puc.cl (R. von Bernhardi). R Available online at www.sciencedirect.com Neurobiology of Disease 14 (2003) 447– 457 www.elsevier.com/locate/ynbdi 0969-9961/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/j.nbd.2003.08.014