Astrocytes were historically classified as supporting cells; however, it is becoming increasingly clear that they actively contribute to neuronal functioning under normal and pathological conditions. ...As interest in the contribution of neuroinflammation to Alzheimer's disease (AD) progression has grown, manipulating glial cells has become an attractive target for future therapies. Astrocytes have largely been under-represented in studies that assess the role of glia in these processes, despite substantial evidence of astrogliosis in AD. The actual role of astrocytes in AD remains elusive, as they seem to adopt different functions dependent on disease progression and the extent of accompanying parenchymal inflammation. Astrocytes may contribute to the clearance of amyloid β-peptide (Aβ) and restrict the spread of inflammation in the brain. Conversely, they may contribute to neurodegeneration in AD by releasing neurotoxins and neglecting crucial metabolic roles. The present review summarizes current evidence on the multi-faceted functions of astrocytes in AD, highlighting the significant scope available for future therapeutic targets.
Environmental manipulations enhance neuroplasticity, with enrichment-induced cognitive improvements linked to increased expression of growth factors and enhanced hippocampal neurogenesis. ...Environmental enrichment (EE) is defined as the addition of social, physical and somatosensory stimulation into an animal's environment via larger group housing, extra objects and, often, running wheels. Previous studies from our laboratory report that physical activity is a potent memory enhancer but that long-term environmental stimulation can be as effective as exercise at ameliorating age-related memory decline. To assess the effects of EE, in the absence of exercise, rats were housed in continuous enriched conditions for 20 months and memory assessed at young, middle aged and aged timepoints. MRI scans were also performed at these timepoints to assess regional changes in grey matter and blood flow with age, and effects of EE upon these measures. Results show an age-related decline in recognition, spatial and working memory that was prevented by EE. A parallel reduction in βNGF in hippocampus, and cell proliferation in the dentate gyrus, was prevented by EE. Furthermore, EE attenuated an age-related increase in apoptosis and expression of pro-inflammatory markers IL-1β and CD68. Long-term EE induced region-specific changes in grey matter intensity and partially rescued age-related reductions in cerebral blood flow. This study demonstrates that sensory enrichment alone can ameliorate many features typical of the ageing brain, such as increases in apoptosis and pro-inflammatory markers. Furthermore, we provide novel data on enrichment-induced regional grey matter alterations and age-related changes in blood flow in the rat.
This article is part of the Special Issue entitled “Neurobiology of Environmental Enrichment”.
•Environmental enrichment without exercise (EE) prevents age-related decline in cognition.•EE prevents age-related decline in spatial and recognition memory.•EE prevents an age-related decrease in cell proliferation in the dentate gyrus.•EE prevents an age-related increase in apoptosis and inflammation in the dentate gyrus.
Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a ...promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Aβ) generation, Aβ aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Aβ levels by these inflammatory mediators.
The role of astrocytes in the progression of Alzheimer's disease (AD) remains poorly understood. We assessed the consequences of ablating astrocytic proliferation in 9 months old double transgenic ...APP23/GFAP‐TK mice. Treatment of these mice with the antiviral agent ganciclovir conditionally ablates proliferating reactive astrocytes. The loss of proliferating astrocytes resulted in significantly increased levels of monomeric amyloid‐β (Aβ) in brain homogenates, associated with reduced enzymatic degradation and clearance mechanisms. In addition, our data revealed exacerbated memory deficits in mice lacking proliferating astrocytes concomitant with decreased levels of synaptic markers and higher expression of pro‐inflammatory cytokines. Our data suggest that loss of reactive astrocytes in AD aggravates amyloid pathology and memory loss, possibly via disruption of amyloid clearance and enhanced neuroinflammation.
Main points
Depletion of proliferating astrocytes in APP23 mice leads to reduced amyloid degradation.
Loss of proliferating astrocytes results in increased memory deficits associated with synaptic and neuronal loss.
Ablation of proliferating astrocytes increases the expression of pro‐inflammatory cytokines.
Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a ...cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, becausewild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.
Nerve Growth Factor (NGF) plays pivotal roles in neuronal survival in the adult mammalian brain and may modulate forms of structural and functional plasticity, including neurogenesis. We have shown ...previously that six weeks of housing in an enriched environment (EE) that did not include access to running wheels resulted in improved recognition memory concomitant with increased NGF expression and neurogenesis in the hippocampus. Here we have attempted to probe a causal link between NGF and the observed enrichment-induced changes in hippocampal function by assessing the effects of six weeks continuous intracerebroventricular (i.c.v.) infusion of NGF on recognition memory and cell proliferation. We report that NGF-infused rats show enhanced recognition memory when compared with vehicle-treated controls. Expression of NGF and its receptor, TrkA, was increased in treated rats, as was expression of the synaptic vesicle protein, synapsin. Finally, we observed an increase in cell proliferation in the dentate gyrus of NGF-treated rats. These data indicate that chronic infusion of NGF can stimulate an improvement in learning and memory that is associated with specific cellular changes in the hippocampus, including synaptogenesis and cell proliferation.
•6 weeks intracerebroventricular NGF infusion enhances recognition memory in the rat.•NGF-treatment enhances expression of NGF, TrkA, and synapsin.•NGF-treatment increases cell proliferation in the dentate gyrus.
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•APP overexpression results in reduced β-catenin nuclear expression.•APP binds to β-catenin in vitro and in vivo.•AD patients show reduced nuclear β-catenin levels.•The expression of ...p-GSK3 is decreased in AD brains.
Accumulating evidence has shown that the processing of the amyloid precursor protein (APP) and the formation of amyloid-β are associated with the canonical Wnt/ β-catenin signalling pathway. It was recently published that the drosophila homologue of APP is a conserved modulator of Wnt PCP signalling, suggesting a potential regulation of this pathway by APP. The aim of this study was to investigate the potential interaction of APP with the canonical Wnt pathway. APP overexpression in N2a cells led to alterations in the subcellular distribution of β-catenin by physically binding to it, preventing its translocation to the nucleus and precluding the transcription of Wnt target genes. In addition, studies in APP transgenic mice and human Alzheimer’s disease (AD) brain tissue showed the cellular co-localization of APP and β-catenin and binding of both proteins, suggesting the formation physical complexes of APP and β-catenin, yet not present in healthy controls. Furthermore, a reduction in the levels of nuclear β-catenin was detected in AD brains compared to controls as well as a decrease in the expression of the inactive phosphorylated Glycogen synthase kinase 3 (GSK3) isoform. Therefore, these findings indicate a reciprocal regulation of Wnt/ β-catenin signalling pathway and APP processing involving a physical interaction between APP and β-catenin.
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