Altered neurogenesis in Alzheimer’s disease Iryna Ziabreva a , Elaine Perry a,b , Robert Perry a , Stephen L. Minger b , Antigoni Ekonomou b , Stefan Przyborski c , Clive Ballard b, 4 a Institute of Ageing and Health, University of Newcastle Upon Tyne, Newcastle General Hospital, Westgate Road, NE4 6BE Newcastle upon Tyne, UK b Wolfson Center for Age-Related Diseases and Institute of Psychiatry, MRC Center for Neurodegeneration, King’s College London, Guy’s Campus, SE1 1UL London, UK c Department of Biological Sciences, University of Durham, South Road, DH1 3LE Durham, UK Received 4 July 2006 Abstract Background: Exciting preliminary work indicates an increase in progenitor activity in the subgranular zone of the dentate gyrus of people with Alzheimer’s disease (AD) compared to that of controls. We examine progenitor activity in the other main progenitor niche, the subventricular zone (SVZ), as well as potential associations with key pathological and neurochemical substrates. Method: Immunocytochemistry techniques utilizing nestin and Musashi1 antibodies were used to examine progenitor activity in the SVZ and to enable comparisons between seven patients with AD and seven controls, based upon the quantification of the percentage area covered, using the Image Pro Plus v.4.1 image analysis system. AD pathology was staged using the Consortium to Establish a Registry for Alzheimer’s Disease and Braak criteria. Choline acetyl transferase (ChAT) was measured in the temporal cortex as an indication of the severity of cortical cholinergic deficits. Glial fibrillary acidic protein (GFAP) was used to label astrocytes. Results: There was a significant ninefold decrease (Z=2.2, P=.046) of Musashi1 immunoreactivity in the SVZ of patients with AD in comparison with that of controls, but there was a significant increase in nestin immunoreactivity in the same region (Z=2.2, P=.028) without any significant change in GFAP immunoreactivity. Reduced ChAT enzymatic activity was the main association of Musashi immunoreactivity (R=À.90, P=.03). Discussion: The current results indicate a significant reduction of progenitor cells (as labeled by Musashi1) in the SVZ of patients with AD, but an increase in GFAP-negative astrocyte- like cells with progenitor characteristics. Cortical cholinergic loss was strongly associated with the reduction of progenitors, with potential implications of important treatment targets. D 2006 Elsevier Inc. All rights reserved. Keywords: Neurogenesis; Alzheimer’s disease; Subventricular zone; Musashi1; Nestin Introduction Stem cells are defined as cells that have the capacity to generate multiple types of differentiated cells (multipotency) and to undergo cell division in which at least one of the daughter cells maintains stem cell potential, hence having the capacity for self-renewal. Particularly in conditions that result in loss of key functional cell groups, such as neurones, the potential therapeutic applications of introducing stem cells to replace the function of those lost in the disease process are enormous. Practical therapies are already on the horizon for some conditions, such as Parkinson’s disease, but an improved understanding of the factors that govern differentiation is needed before the introduction of stem cells into the brain becomes a viable option for the treatment of dementia. Although it has been widely recognized that a stem cell population is maintained in some adult tissues, until the last decade, it was thought that the adult brain was 0022-3999/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.jpsychores.2006.07.017 4 Corresponding author. Wolfson Center for Age-Related Diseases, Wolfson Building, King’s College London, Guy’s Campus, SE1 1UL London, UK. Tel.: +44 20 7848 6568; fax: +44 20 7848 6569. E-mail address: clive.ballard@kcl.ac.uk (C. Ballard). Journal of Psychosomatic Research 61 (2006) 311 – 316