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Stage-Specific Changes in Neurogenic and Glial Markers in Alzheimer's Disease

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


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BACKGROUND: Reports of altered endogenous neurogenesis in people with Alzheimer's disease (AD) and transgenic AD models have suggested that endogenous neurogenesis may be an important treatment target, but there is considerable discrepancy among studies. We examined endogenous neurogenesis and glia changes across the range of pathologic severity of AD in people with and without dementia to address this key question.METHODS: Endogenous neurogenesis and glia in the subventricular zone and dentate gyrus neurogenic niches were evaluated using single and double immunohistochemistry and a validated antibody selection for stage-specific and type-specific markers in autopsy tissue from a representative cohort of 28 participants in the Medical Research Council Cognitive Function and Ageing Study. Immunopositive cells were measured blinded to diagnosis using bright-field and fluorescent microscopy.RESULTS: The number of newly generated neurons significantly declined only in the dentate gyrus of patients with severe tau pathology. No other changes in other neurogenic markers were observed in either of the neurogenic niches. Alterations in astrocytes and microglia were also observed in the dentate gyrus across the different stages of tau pathology. No change in any of the markers was observed in individuals who died with dementia compared with individuals who did not die with dementia.CONCLUSIONS: Alterations in endogenous neurogenesis appeared to be confined to a reduction in the generation of new neurons in the dentate gyrus of patients with AD and severe neurofibrillary tangle pathology and were accompanied by changes in the glia load. These data suggest that intervention enhancing endogenous neurogenesis may be a potential therapeutic target in AD.

Publication metadata

Author(s): Ekonomou A, Savva GM, Brayne C, Forster G, Francis PT, Johnson M, Perry EK, Attems J, Somani A, Minger SL, Ballard CG, on behalf of The Medical Research Council Cognitive Function and Ageing Neuropathology Study

Publication type: Article

Publication status: Published

Journal: Biological Psychiatry

Year: 2015

Volume: 77

Issue: 8

Pages: 711-719

Print publication date: 15/04/2015

Online publication date: 09/06/2014

Acceptance date: 23/05/2014

ISSN (print): 0006-3223

ISSN (electronic): 1873-2402

Publisher: Elsevier


DOI: 10.1016/j.biopsych.2014.05.021


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Funder referenceFunder name
Age-related Disease Award
Bristol-Myer Squibb
Cambridge Brain Bank
Janssen Alzheimer Immunotherapy
NIHR Cambridge Biomedical Research Centre
Oxford Biomedical Research Centre
United Kingdom National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing
University of Sheffield
Brains for Dementia Research
Cambridgeshire and Peterborough NIHR Collaborations for Leadership in Applied Health Research and Care
Department of Health
Nottingham University Hospitals National Health Service (NHS) Trust
Sheffield Teaching Hospitals NHS Foundation Trust
Thomas Willis Oxford Brain Collection
Walton Centre NHS Foundation Trust, Liverpool
309Research Into Ageing-Age UK
MRC U.1052.00.0013Medical Research Council
MRC/G9901400Medical Research Council