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Cited by 377Neurogenesis and neuroplasticity mechanismsAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease

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Rodríguez, José J., Jones, Victoria C., Tabuchi, Masashi, Allan, Stuart M., Knight, Elysse M., LaFerla, Frank M., Oddo, Salvatore, Verkhratsky, Alexei·2008·PLoS ONE
DOI 10.1371/journal.pone.0002935PMC PMC2492828
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Abstract

It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (beta-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of beta-amyloid plaques and an increase in the number of beta-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.

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  • Destruction of primary cilia in the cortex and hippocampus can disrupt learning, memory, and recognition of novel objects, thereby impairing cognitive function.

    “For instance, the destruction of primary cilia in the cortex and hippocampus can disrupt learning, memory, and recognition of novel objects, thereby impairing cognitive function (Rodríguez et al. 2008;Armato et al. 2013).”

    From Changes of the Primary Cilia in Alzheimer's Disease Pathogenesis (2025) · cites this paper as Rodríguez et al. 2008

    The Discussion (page unavailable) links reduced hippocampal neurogenesis to certain learning and memory impairments. It does not address destruction of primary cilia in the cortex or hippocampus, or recognition of novel objects; searches for those terms found no supporting passage. The cognitive effect is thus supported only for a different proposed mechanism. (LLM, conf=0.84)

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Authors
Rodríguez, J. J., Jones, V. C., Tabuchi, M., Allan, S. M., Knight, E. M., LaFerla, F. M., Oddo, S., & Verkhratsky, A.
Affiliations
  • University of Manchester (GB)
  • University of California, Irvine (US)
  • Czech Academy of Sciences (CZ)
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2008-08-13
Volume
3
Issue
8
Pages
e2935
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0002935
PMC
PMC2492828
OpenAlex
W2015387012
Cited by
377
References
6
Citations by year
2026: 6 · 2025: 17 · 2024: 19 · 2023: 23 · 2022: 17 · 2021: 15 · 2020: 20 · 2019: 27 · 2018: 18 · 2017: 25 · 2016: 26 · 2015: 22 · 2014: 21 · 2013: 30 · 2012: 28
FWCI
6.42
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CLOK (University of Central Lancashire) (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • Research Explorer (The University of Manchester) (submittedVersion)
Funders
Alzheimer's Research Trust (ART/PG2004A/1)
Topics
  • Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
adult neurogenesis, dentate gyrus, Alzheimer's disease, 3xTg-AD mice, subgranular zone, amyloid plaques, sex differences, hippocampus, presenilin 1, tau protein, amyloid precursor protein, glial fibrillary acidic protein, histone H3 phosphorylation, neuronal proliferation, cognitive impairment, neurodegeneration
MeSH terms
Aging, Alzheimer Disease, Serum Amyloid A Protein, Animals, Disease Models, Animal, Female, Humans, Male, Mice, Transgenic, tau Proteins, Dentate Gyrus, Amino Acid Substitution, Mice, Presenilins

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