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Neurogenic abnormalities in Alzheimer's disease differ between stages of neurogenesis and are partly related to cholinergic pathology

Lookup NU author(s): Emeritus Professor Elaine Perry, Mary Johnson, Emeritus Professor Robert Perry, Dr Clive Ballard, Professor Johannes Attems


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Neurogenesis occurs in the subventricular zone and the sub-granular layer of the hippocampus and is thought to take place in 5 stages, including proliferation, differentiation, migration, targeting, and integration phases, respectively. In Alzheimer's disease (AD) both increased and decreased neurogenesis has been reported and cholinergic activity is assumed to be involved in neurogenesis. The aim of this study was to systematically assess different phases of neurogenesis and their relation to AD and cholinergic pathology. We investigated post-mortem brain tissue from 20 AD patients and 21 non-demented controls that was neuropathologically characterized according to standardized criteria. Hippocampal sections were stained with antibodies against neurogenic markers Musashi-1, nestin, PSA-NCAM, doublecortin, and beta-III-tubulin as well as ChAT (choline-acetyltransferase). Using image analysis immunoreactivity was assessed in the subventricular zone, the sub-granular layer, and the granule cell layer by determining the integrated optical density. In the sub-granular layer and the granule cell layer Musashi-1 and ChAT immunoreactivities were significantly lower in AD and decreased with increasing Braak stages. Conversely, immunorreactivities of both nestin and PSA-NCAM were significantly higher in AD and increased with increasing Braak stages while no changes were seen for doublecortin and beta-III-tubulin, except for significantly higher doublecortin levels in the granule cell layer of AD cases. Of note, Musashi-1 immunoreactivity significantly correlated with ChAT immuonoreactivity across different Braak stages. In the subventricular zone only nestin immunoreactivity was significantly higher in AD and significantly increased with increasing Braak stages, while no significant differences were seen for all other markers. Our finding of a reduction of ChAT and Musashi-1 levels in AD is compatible with the assumption that cholinergic pathology per se has a detrimental influence on neurogenesis. We conclude that neurogenic abnormalities in AD differ between phases and areas of neurogenesis and stages of AD; while hippocampal stem cells (Musashi-1) decrease, proliferation (nestin) increases and differentiation/migration phase as well as axonal/dendritic targeting (doublecortin and beta-III-tubulin) remains virtually unchanged. This suggests an attenuation of stem cells together with compensatory increased proliferation that, however, does not result in an increased number of migratory neuroblasts and differentiated neurons in AD.

Publication metadata

Author(s): Perry EK, Johnson M, Ekonomou A, Perry RH, Ballard C, Attems J

Publication type: Article

Publication status: Published

Journal: Neurobiology of Disease

Year: 2012

Volume: 47

Issue: 2

Pages: 155-162

Print publication date: 05/04/2012

ISSN (print): 0969-9961

ISSN (electronic): 1095-953X

Publisher: Academic Press


DOI: 10.1016/j.nbd.2012.03.033


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Funder referenceFunder name
Alzheimer Research Trust
Alzheimer's Research Trust as part of the brains for Dementia Research Project
Alzheimer's Society
Newcastle NIHR Biomedical Research Centre In Ageing and Age Related Diseases
UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
G0400074UK Medical Research Council