Increased proliferation reflects glial and vascular-associated changes, but not neurogenesis in the presenile Alzheimer hippocampus (original) (raw)
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Microscopy Research and Technique, 2005
Immunohistochemical localizing of the proliferation of Ki67 nuclei and doublecortin positive cells were performed in the prefrontal cortex of normal aged and vascular dementia (multiple infarct dementia) patients. Positive Ki67 nuclei and doublecortin positive cells were observed in both groups, with slightly higher density in the prefrontal cortex of vascular dementia. When the Ki67 sites were superimposed with the neuronal specific enolase localizations, only about 5% of the cells was doubly labeled, indicating few proliferating cells were neurons. This percentage did not vary between specimens of normal aging and those of vascular dementia.
Neurobiology of Aging, 2017
In Alzheimer's disease, the hippocampus is characterized by abundant deposition of amyloid peptides (amyloid β [Aβ]) and neuroinflammation. Adult hippocampal neurogenesis (AHN) is a form of plasticity that contributes to cognition and can be influenced by either or both pathology and neuroinflammation. Their interaction has been studied before in rapidly progressing transgenic mouse models with strong overexpression of amyloid precursor protein (APP) and/ or presenilin 1. So far, changes in AHN and neuroinflammation remain poorly characterized in slower progressing models at advanced age, which approach more closely sporadic Alzheimer's disease. Here, we analyzed 10-to 26-month-old APP.V717I mice for possible correlations between Aβ pathology, microglia, and AHN. The age-related increase in amyloid pathology was closely paralleled by microglial CD68 upregulation, which was largely absent in age-matched wild-type littermates. Notably, aging reduced the AHN marker doublecortin, but not calretinin, to a similar extent in wild-type and APP.V717I mice between 10 and 26 months. This demonstrates that AHN is influenced by advanced age in the APP.V717I mouse model, but not by Aβ and microglial activation.
Changes in neurogenesis in dementia and Alzheimer mouse models: are they functionally relevant?
European Archives of Psychiatry and Clinical Neuroscience, 2007
Alzheimer's disease and related dementias are devastating disorders that lead to the progressive decline of cognitive functions. Characteristic features are severe brain atrophy, paralleled by accumulation of beta amyloid and neurofibrillary tangles. With the discovery of neurogenesis in the adult brain, the hopes have risen that these neurodegenerative conditions could be overcome, or at least ameliorated, by the generation of new neurons. The location of the adult neurogenic zones in the hippocampus and the lateral ventricle wall, close to corpus callosum and neocortex, indicates strategic positions for potential repair processes. However, we also need to consider that the generation of new neurons is possibly involved in cognitive functions and could, therefore, be influenced by disease pathology. Moreover, aberrant neurogenic mechanisms could even be a part of the pathological events of neurodegenerative diseases. It is the scope of this review to summarize and analyze the recent data from neurogenesis research with respect to Alzheimer's disease and its animal models.
Altered neurogenesis in Alzheimer's disease
Journal of Psychosomatic Research, 2006
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 astrocytelike cells with progenitor characteristics. Cortical cholinergic loss was strongly associated with the reduction of progenitors, with potential implications of important treatment targets. D
Hippocampal neurogenesis during normal and pathological aging
Psychoneuroendocrinology, 2007
It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.
Neurochemical Research, 2004
In response to central nervous system (CNS) injury, and more discretely so also during aging, astrocytes become reactive and increase their expression of the intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin. Studies of mice deficient in astrocytic intermediate filaments have provided insights into the function of reactive gliosis. Recently we demonstrated robust integration of retinal transplants (1) and increased posttraumatic synaptic regeneration (2) in GFAP )/) Vim )/) mice, suggesting that modulation of astrocyte activity affects the permissiveness of the CNS environment for regeneration. Neurogenesis in the adult mammalian CNS is restricted to essentially two regions, the hippocampus and the subventricular zone. Here, we assessed neurogenesis in the hippocampus of 18-month-old GFAP )/) Vim )/) mice. In the granular layer of the dentate gyrus, cell proliferation/survival was 34% higher and neurogenesis 36% higher in GFAP )/) Vim )/) mice than in wildtype controls. These findings suggest that the adult hippocampal neurogenesis in healthy old mice can be increased by modulating astrocyte reactivity.
Acta Histochemica, 2009
Neurogenesis in the adult hippocampus is differentially influenced by the genetic background. We examined the differences in Ki-67 (a proliferating cell marker) and doublecortin (DCX; an immature progenitor cell marker) immunolabelling in the dentate gyrus (DG) of the adult hippocampus in three strains of mice (ICR, C57BL/6, and BALB/c) to evaluate the effect of genetic background on adult hippocampal neurogenesis. All strains showed constitutive immunoreactivity of either Ki-67 or DCX in the DG of the adult hippocampus. C57BL/6 mice showed significantly higher levels of Ki-67-immunopositive cells in the subgranular zone (SGZ) of the DG (approximately 2.2-fold) compared to ICR and BALB/c mice. The greatest number of DCX-immunopositive cells was found in C57BL/6 (approximately 1.6-fold), which differed significantly from ICR and BALB/c mice. However, there was no significant difference in the number of Ki-67- and DCX-immunopositive cells between BALB/c and ICR mice. Genetic differences with respect to certain aspects of hippocampal neurogenesis in adult mice may influence hippocampal functions, including learning and memory.
Neural plasticity, 2014
Microglia and astrocytes contribute to Alzheimer's disease (AD) etiology and may mediate early neuroinflammatory responses. Despite their possible role in disease progression and despite the fact that they can respond to amyloid deposition in model systems, little is known about whether astro- or microglia can undergo proliferation in AD and whether this is related to the clinical symptoms or to local neuropathological changes. Previously, proliferation was found to be increased in glia-rich regions of the presenile hippocampus. Since their phenotype was unknown, we here used two novel triple-immunohistochemical protocols to study proliferation in astro- or microglia in relation to amyloid pathology. We selected different age-matched cohorts to study whether proliferative changes relate to clinical severity or to neuropathological changes. Proliferating cells were found across the hippocampus but never in mature neurons or astrocytes. Almost all proliferating cells were co-label...
Neurogenesis in Human Hippocampus: Implications for Alzheimer Disease Pathogenesis
Neuroembryology and Aging, 2006
Alzheimer disease (AD) is the most common cause of dementia, and its prevalence is directly related to age . Moreover, the increasing life expectancy, rising from 50 years at the beginning of the last century to approximately 80 years today, inevitably brings a higher incidence of age-related illnesses, including AD, resulting in an increase from 4 million individuals currently affected with AD in the United States to an estimated 14 million by 2050 . In spite of these figures, the lack of progress toward effective therapy is striking.