Elevated connexin43 immunoreactivity at sites of amyloid plaques in alzheimer's disease

Nagy, J.I.; Li, Wei; Hertzberg, Elliot L.; Marotta, Charles A.

doi:10.1016/0006-8993(95)01526-4

Cited by 162 publications

(124 citation statements)

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“…Gap junctional intercellular communication (GJIC) has been implicated in the homeostatic regulation of cell growth and differentiation [9], and Cx43 of Cxs was expressed in the CNS [16]. Here we investigated the relationship between GJIC and MAPK pathway in neuronal stem cell differentiation and neuronal stem cell derived cells with treatment of TPA.…”

Section: Discussionmentioning

confidence: 99%

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

Yang

Cho

Ahn

et al. 2005

The Journal of Veterinary Medical Science

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ABSTRACT. Gap junctional intercellular communications (GJIC) contributes to neural function in development and differentiation of CNS. In this study, we have investigated the expression of GJIC during the differentiation of neuronal stem cells and 12-Ø-tetradecanoylphorbol-13-acetate (TPA)-induced neuronal stem cell-derived cells from rat brain. During neuronal stem cell differentiation, expressions of Cx43 and 32 were increased for the duration of 72 hr, however the effect were decreased on the 7d. In the neuronal stem cell-derived cells, pretreatments with p38 MAP kinase inhibitor, SB203580, and MEK inhibitor, PD98059, could protect GJIC against TPA-induced inhibition of GJIC. Our data suggest that GJIC plays an important role during neuronal stem cell differentiation, and ERK1/2 and p38 MAP kinase signaling pathway may be closely related functionally to regulate gap junction in rat neuronal stem cell-derived cells. Neuronal stem cells are able to differentiate into astrocytes, neurons, and oligodendrocytes [3,10,23], when given the appropriate signals [2,7]. During the stage where the brain develops, gap junctional intercellular communication (GJIC) allows the diffusional exchange of ions and metabolites for communication between neighboring cells [8,14,20]. Connexin 32 and 43 were expressed in the neurons of adult rat or mouse [15,17], and Cx43 was the most abundant gap junction protein in the CNS [4,5]. However, no study has yet been performed to the role of gap junctions in rat neuronal stem cell differentiation. In the present study, we have examined protein expression of Cx43 and Cx32 during the neuronal stem cell differentiation and induction of Cx43 and Cx32. This can be elicited in neuronal stem cell-derived cells by treatment with 12-O-tetradecanoylphorbol-13-acetate (TPA) and this induction showed that it can be prevented by the p38 MAP-Kinase inhibitor SB203580 and the MEK inhibitor PD98059. MATERIALS AND METHODSCell culture: Neuronal stem cells were prepared by culturing cells from cerebrum of embryonic day 17 (E17) Sprague-Dawley rat (Bio Genomics, Korea) fetus. Briefly, fresh cerebrums were dissociated in the presence of trypsin and DNase I and planted on a Petri dish (Nunc, IL). Cells were seeded at a density of 1~5 × 10 6 cells/ml in a mixture (1:1) of Dulbecco's modified Eagle's medium/Ham's F12 (DMEM/F12; Gibco) replenished with 2% B27 (Gibco), gentamycin (50 µg/ml), anti-PPLO (pleuro-pneumonia-like organism) reagent (100 µg/ml), recombinant human basic fibroblast growth factor (bFGF 20 ng/ml, Sigma), and epidermal growth factor (10 ng/ml).Scrape loading/ dye transfer (SL/DT) assay: Cells were treated with TPA for 1 hr. The GJIC assay was conducted at non-cytotoxic dose levels of the samples, as determined by the MTT assay. Following incubation, the cells were washed twice with 2 ml of PBS, Lucifer yellow was added to the washed cells and three scrapes were made with a surgical steel-bladed scalpel at low light intensities. These three scrapes were performed to ensure that the scrape travers...

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Section: Discussionmentioning

confidence: 99%

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

Yang

Cho

Ahn

et al. 2005

The Journal of Veterinary Medical Science

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“…Both resting calcium and intracellular calcium waves in astrocytes near plaques are increased, indicating that the astrocyte network contributes to AD pathology (Kuchibhotla, Lattarulo, Hyman, & Bacskai, 2009). Additionally, gap junctions between astrocytes are altered in AD (Nagy, Li, Hertzberg, & Marotta, 1996). Increased glutamate and ATP release has been linked to altered gap junction expression, suggesting that blocking hemichannels in neurons could be neuroprotective in AD (Orellana et al, 2011).…”

Section: Astrocytes In the Diseased Brain Are Central To Neuropathologymentioning

confidence: 99%

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

Liu

Teschemacher

Kasparov

2017

Glia

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Astrocytes are key homeostatic cells of the central nervous system. They cooperate with neurons at several levels, including ion and water homeostasis, chemical signal transmission, blood flow regulation, immune and oxidative stress defense, supply of metabolites and neurogenesis. Astroglia is also important for viability and maturation of stem‐cell derived neurons. Neurons critically depend on intrinsic protective and supportive properties of astrocytes. Conversely, all forms of pathogenic stimuli which disturb astrocytic functions compromise neuronal functionality and viability. Support of neuroprotective functions of astrocytes is thus an important strategy for enhancing neuronal survival and improving outcomes in disease states. In this review, we first briefly examine how astrocytic dysfunction contributes to major neurological disorders, which are traditionally associated with malfunctioning of processes residing in neurons. Possible molecular entities within astrocytes that could underpin the cause, initiation and/or progression of various disorders are outlined. In the second section, we explore opportunities enhancing neuroprotective function of astroglia. We consider targeting astrocyte‐specific molecular pathways which are involved in neuroprotection or could be expected to have a therapeutic value. Examples of those are oxidative stress defense mechanisms, glutamate uptake, purinergic signaling, water and ion homeostasis, connexin gap junctions, neurotrophic factors and the Nrf2‐ARE pathway. We propose that enhancing the neuroprotective capacity of astrocytes is a viable strategy for improving brain resilience and developing new therapeutic approaches.

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“…The most prominent indication of connexin changes in Alzheimer's disease is that increased immunoreactivity of Cx43 has been found at Aβ plaque levels in the post-mortem brains of AD patients, which coincides with the presence of gap junctions between astrocytic processes that are adjacent to dystrophic neuronal processes that are present in plaque areas at the ultrastructural level [11]. This Cx43 puncta enrichment has also been found within cadaveric brain sections from AD patients and is detected intermingled with strongly GFAP-positive astrocytic processes that infiltrate Aβ plaques [12]. These features have also been shown to be present in Cx30, though to a lower extent.…”

Section: Commentarymentioning

confidence: 79%

“…In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled by dystrophic neurites [12,13]. Glutamate and ATP can also promote activation of neuronal NMDA and purinergic receptors further leading to Ca 2+ overload (5) and the activation of intracellular neurotoxic cascades resulting in neurodegeneration (6).…”

Section: Commentarymentioning

confidence: 99%

“…In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled by dystrophic neurites [12,13].Figure 1: Astroglial hemichannels contribute to neuronal degeneration in a murine model of AD. In the hippocampus of APP/PS1 mice, Cx43 hemichannels (HCs) are activated in astrocytes both "far" and "close" to Aβ plaques triggered by high [Ca 2+ ]i, while Panx1 is only a minor contributor to HC activity triggered by proinflammatory cytokines from activated microglia (1) restricted in astrocytes close to plaques.…”

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confidence: 99%

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New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

Yi¹,

Koulakoff²,

Giaume³

2017

J Cell Signal

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CommentaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly and characterized by progressive memory loss, behavioral deficits and significant personality alterations [1,2]. The histopathological hallmarks of AD include Aβ plaques, neurofibrillary tangles, neuronal death and synapse loss. One significant feature of Aβ accumulation is the strong reactive gliosis associated with the Aβ plaques themselves [3,4], however, understanding of the properties and functions of astrocytes in AD has only begun to emerge in recent years.In the brain, astrocytes possess the highest levels of connexin (Cx) expression, with Cx43 and Cx30 being the most abundant [5,6]. Cxs are the proteins that form gap junction channels (GJCs) and hemichannels (HCs). Besides Cxs, HCs can be formed by another family of functionally related proteins, pannexins (Panxs), which share the same transmembrane topology as Cxs but have divergent primary sequences [7]. Cxs and Panxs oligomerize into hexameres that isolate a large non-selective pore in the membrane allowing for the diffusion of small molecules (e.g. ions, small signaling molecules and metabolic substrates) between the cell cytoplasm and the extracellular medium. In addition, most Cx HCs dock head-to-head between adjacent cells to form intercellular channels that constitute GJCs, while endogenously expressed Panx HCs do not [8,9]. In the brain, astrocytes provide trophic and metabolic support to neurons throughout the astrocytic network via gap junction communication which comprise of over several hundreds of astrocytes [10]. In brain pathologies, for instance in AD, reactive astrogliosis has been associated with changes in the expression and function of connexins. Increased expression of Cxs has been found in astrocytes that are in contact with amyloid plaques in vivo within the brains of AD patients and also in AD animal models. The most prominent indication of connexin changes in Alzheimer's disease is that increased immunoreactivity of Cx43 has been found at Aβ plaque levels in the post-mortem brains of AD patients, which coincides with the presence of gap junctions between astrocytic processes that are adjacent to dystrophic neuronal processes that are present in plaque areas at the ultrastructural level [11]. This Cx43 puncta enrichment has also been found within cadaveric brain sections from AD patients and is detected intermingled with strongly GFAP-positive astrocytic processes that infiltrate Aβ plaques [12]. These features have also been shown to be present in Cx30, though to a lower extent. This is also the case in AD animal models. In a murine model of familial AD (APPSwe/PS1dE9; or termed APP/PS1), these transgenic mice exhibit a variety of changes, including an increase in Cx43 or Cx30 immunoreactivity at Aβ plaque levels in the hippocampus and cortex of APP/PS1 mice older than 4 months. These connexin immunoreactivities have been found to be concentrated in bright and large puncta at astrocytic processes that infiltrate the plaque core, and are encircled...

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Elevated connexin43 immunoreactivity at sites of amyloid plaques in alzheimer's disease

Cited by 162 publications

References 14 publications

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

Role of Gap Junctional Intercellular Communication (GJIC) through p38 and ERK1/2 Pathway in the Differentiation of Rat Neuronal Stem Cells

Astroglia as a cellular target for neuroprotection and treatment of neuro‐psychiatric disorders

New Insights on Astroglial Connexins as a Therapeutic Target for Alzheimer's Disease

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