Activation of oncogenic pathways in degenerating neurons in Alzheimer disease Xiongwei Zhu a , Arun K. Raina a , Heather Boux b , Zachary L. Simmons a , Atsushi Takeda a , Mark A. Smith a, * a Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44196, USA b StressGen Biotechnologies Corporation, Inc, Victoria, British Columbia, Canada Received 13 April 1999; accepted 6 June 1999 Abstract A number of recent ®ndings have highlighted the similarities between neurogenesis during development and neurodegeneration during Alzheimer disease. In fact, neuronal populations that are known to degenerate in Alzheimer disease exhibit phenotypic changes characteristic of cells re-entering the cell division cycle. In this study, we extended these ®ndings by investigating components of the cell cycle, known to trigger progression through G1 through activation of signal transduction cascades. Speci®cally, we found that proteins implicated in G1 transition, namely Cdc42/Rac, are upregulated in select neuronal populations in cases of Alzheimer disease in comparison to age-matched controls. Importantly, Cdc42/Rac shows considerable overlap with early cytoskeletal abnormalities suggesting that these changes are an extremely proximal event in the pathogenesis of the disease. Given the functional role of Cdc42/Rac in various cellular processes known to be perturbed in Alzheimer disease, namely cytoskeletal organization, oxidative balance, and oncogenic signaling, it is likely that increased neuronal Cdc42/Rac is highly signi®cant in relation to the pathogenic process and contributes to neuronal degeneration. In fact, these ®ndings suggest that Alzheimer disease is an oncogenic process. 7 2000 ISDN. Published by Elsevier Science Ltd. All rights reserved. 1. Introduction We, and others, have demonstrated ectopic ex- pression of mitosis-speci®c proteins in neuronal popu- lations aected in Alzheimer disease (AD) [1±7]. Aside from increased phosphorylation of the cytoskeletal as- sociated protein t [8], the consequences of such a re- entrant phenotype remain to be established. However, cell cycle re-entry and/or attempts to proliferate may form part of a universal in vivo pathological process in terminally dierentiated neurons [9] that is associ- ated with oxidative stress-induced neuronal death [10]. In AD, the stimulus for proliferation seems to orig- inate proximal to the plasma membrane through acti- vation of the ras pathway [9]. Cdc42 and Rac, belonging to the Rho family of small GTPases, act as molecular switches that, in re- sponse to extracellular signals, induce coordinated changes in the organization of the cytoskeleton. Fur- thermore, Cdc42 and/or Rac-induced gene transcrip- tion drives a wide variety of biological responses including cell cycle progression, morphogenesis and/or apoptosis [11,12]. For example, Cdc42 and Rac trigger progression through G1 phase of the cell cycle when introduced into quiescent ®broblasts [13] and are essential for serum-induced G1 progression and for ras-induced cell transformation [14±16]. Additionally, it is well established that Cdc42 and Rac are important upstream regulators of the protein kinase cascade that control the SAPK/JNK and p38 activity [17,18]. There is also emerging evidence that the SAPK/JNK path- way is involved in mediating cell death following ex- Int. J. Devl Neuroscience 18 (2000) 433±437 0736-5748/00/$20.00 7 2000 ISDN. Published by Elsevier Science Ltd. All rights reserved. PII: S0736-5748(00)00010-1 www.elsevier.com/locate/ijdevneu * Corresponding author. Tel.: +1-216-368-3670; fax: +1-216-368- 8964. E-mail address: mas21@po.cwru.edu (M.A. Smith).