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Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease.

Farfara D, Lifshitz V, Frenkel D - J. Cell. Mol. Med. (2008)

Bottom Line: The main cause of AD is generally attributed to the increased production and accumulation of amyloid-beta (Abeta), in association with neurofibrillary tangle (NFT) formation.Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries.The focus of this review is on glial cells and their diversity properties in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Alzheimer's disease (AD) affects more than 18 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-beta (Abeta), in association with neurofibrillary tangle (NFT) formation. Increased levels of pro-inflammatory factors such as cytokines and chemokines, and the activation of the complement cascade occurs in the brains of AD patients and contributes to the local inflammatory response triggered by senile plaque. The existence of an inflammatory component in AD is now well known on the basis of epidemiological findings showing a reduced prevalence of the disease upon long-term medication with anti-inflammatory drugs, and evidence from studies of clinical materials that shows an accumulation of activated glial cells, particularly microglia and astrocytes, in the same areas as amyloid plaques. Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries. Dysfunction of glial cells may promote neurodegeneration and, eventually, the retraction of neuronal synapses, which leads to cognitive deficits. The focus of this review is on glial cells and their diversity properties in AD.

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Activation of the glial cell response toward the formation of senile plaque in Alzheimer's disease. The overproduction and extracellular deposition of amyloid β-peptide (AβP) and an intracellular deposition of neurofibrillary tangles (NFT) initiates the pathogenesis of Alzheimer's disease (AD). The production of complement components (C1q, C3 and C5) is the first stage in response to Aβ deposition, resulting in the attraction and activation of microglial cells. Both microglial cells and astrocytes produce multiple pro-inflammatory and neurotoxic factors: transforming growth factor (TGF)-1; tumour necrosis factor (TNF)-α; interleukin-1 (IL-1); CC-chemokine ligand (CCL); antichymotrypsin (ACT); reactive oxygen species (ROS) and cyclooxygenase 2 (COX2). Activated microglial cells express various scavenger receptors (SRs) that mediate phagocytosis of Aβ, such as CD36, SR-A. Microglial cells can also degrade Aβ by releasing Aβ-degrading enzymes, such as insulin-degrading enzyme (IDE).
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fig01: Activation of the glial cell response toward the formation of senile plaque in Alzheimer's disease. The overproduction and extracellular deposition of amyloid β-peptide (AβP) and an intracellular deposition of neurofibrillary tangles (NFT) initiates the pathogenesis of Alzheimer's disease (AD). The production of complement components (C1q, C3 and C5) is the first stage in response to Aβ deposition, resulting in the attraction and activation of microglial cells. Both microglial cells and astrocytes produce multiple pro-inflammatory and neurotoxic factors: transforming growth factor (TGF)-1; tumour necrosis factor (TNF)-α; interleukin-1 (IL-1); CC-chemokine ligand (CCL); antichymotrypsin (ACT); reactive oxygen species (ROS) and cyclooxygenase 2 (COX2). Activated microglial cells express various scavenger receptors (SRs) that mediate phagocytosis of Aβ, such as CD36, SR-A. Microglial cells can also degrade Aβ by releasing Aβ-degrading enzymes, such as insulin-degrading enzyme (IDE).

Mentions: Although Aβ is the major component of the amyloid deposits, other molecules are also associated with these deposits (e.g. ferritin, components of the complement pathway, α1-antichymotrypsin, α2-macroglobulin, low-density lipoprotein [LDL] receptor-related protein, APP, acetylcholinesterase, laminin, glycosaminoglycans and the apolipoproteins E and J) [11–13]. Aβ can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, mislocalization and accumulation. Intracellular abnormally phosphorylated tau and Aβ exhibit synergistic effects that finally lead to an acceleration of neurodegenerative mechanisms involved in metabolism, cellular detoxification, mitochondrial dysfunction and energy deficiency, which result in the formation of neuritic plaques [1]. Such plaques are also closely associated with microglia that express surface antigens associated with activation, and surrounded by reactive astrocytes displaying abundant glial filaments. The microglia are usually within and adjacent to the central amyloid core of the neuritic plaque, whereas the astrocytes often ring the outside of the plaque with some of these processes centripetal to the amyloid core [14] (Fig. 1). The time extent that it takes to develop such a neuritic plaque is unknown, but these lesions probably evolve very gradually over a substantial time, perhaps several years. The dialogue between the microglia and astro-cyte play an important role in shaping the immune response surrounding the amyloid plaques.


Neuroprotective and neurotoxic properties of glial cells in the pathogenesis of Alzheimer's disease.

Farfara D, Lifshitz V, Frenkel D - J. Cell. Mol. Med. (2008)

Activation of the glial cell response toward the formation of senile plaque in Alzheimer's disease. The overproduction and extracellular deposition of amyloid β-peptide (AβP) and an intracellular deposition of neurofibrillary tangles (NFT) initiates the pathogenesis of Alzheimer's disease (AD). The production of complement components (C1q, C3 and C5) is the first stage in response to Aβ deposition, resulting in the attraction and activation of microglial cells. Both microglial cells and astrocytes produce multiple pro-inflammatory and neurotoxic factors: transforming growth factor (TGF)-1; tumour necrosis factor (TNF)-α; interleukin-1 (IL-1); CC-chemokine ligand (CCL); antichymotrypsin (ACT); reactive oxygen species (ROS) and cyclooxygenase 2 (COX2). Activated microglial cells express various scavenger receptors (SRs) that mediate phagocytosis of Aβ, such as CD36, SR-A. Microglial cells can also degrade Aβ by releasing Aβ-degrading enzymes, such as insulin-degrading enzyme (IDE).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4401126&req=5

fig01: Activation of the glial cell response toward the formation of senile plaque in Alzheimer's disease. The overproduction and extracellular deposition of amyloid β-peptide (AβP) and an intracellular deposition of neurofibrillary tangles (NFT) initiates the pathogenesis of Alzheimer's disease (AD). The production of complement components (C1q, C3 and C5) is the first stage in response to Aβ deposition, resulting in the attraction and activation of microglial cells. Both microglial cells and astrocytes produce multiple pro-inflammatory and neurotoxic factors: transforming growth factor (TGF)-1; tumour necrosis factor (TNF)-α; interleukin-1 (IL-1); CC-chemokine ligand (CCL); antichymotrypsin (ACT); reactive oxygen species (ROS) and cyclooxygenase 2 (COX2). Activated microglial cells express various scavenger receptors (SRs) that mediate phagocytosis of Aβ, such as CD36, SR-A. Microglial cells can also degrade Aβ by releasing Aβ-degrading enzymes, such as insulin-degrading enzyme (IDE).
Mentions: Although Aβ is the major component of the amyloid deposits, other molecules are also associated with these deposits (e.g. ferritin, components of the complement pathway, α1-antichymotrypsin, α2-macroglobulin, low-density lipoprotein [LDL] receptor-related protein, APP, acetylcholinesterase, laminin, glycosaminoglycans and the apolipoproteins E and J) [11–13]. Aβ can adversely affect distinct molecular and cellular pathways, thereby facilitating tau phosphorylation, aggregation, mislocalization and accumulation. Intracellular abnormally phosphorylated tau and Aβ exhibit synergistic effects that finally lead to an acceleration of neurodegenerative mechanisms involved in metabolism, cellular detoxification, mitochondrial dysfunction and energy deficiency, which result in the formation of neuritic plaques [1]. Such plaques are also closely associated with microglia that express surface antigens associated with activation, and surrounded by reactive astrocytes displaying abundant glial filaments. The microglia are usually within and adjacent to the central amyloid core of the neuritic plaque, whereas the astrocytes often ring the outside of the plaque with some of these processes centripetal to the amyloid core [14] (Fig. 1). The time extent that it takes to develop such a neuritic plaque is unknown, but these lesions probably evolve very gradually over a substantial time, perhaps several years. The dialogue between the microglia and astro-cyte play an important role in shaping the immune response surrounding the amyloid plaques.

Bottom Line: The main cause of AD is generally attributed to the increased production and accumulation of amyloid-beta (Abeta), in association with neurofibrillary tangle (NFT) formation.Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries.The focus of this review is on glial cells and their diversity properties in AD.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

ABSTRACT
Alzheimer's disease (AD) affects more than 18 million people worldwide and is characterized by progressive memory deficits, cognitive impairment and personality changes. The main cause of AD is generally attributed to the increased production and accumulation of amyloid-beta (Abeta), in association with neurofibrillary tangle (NFT) formation. Increased levels of pro-inflammatory factors such as cytokines and chemokines, and the activation of the complement cascade occurs in the brains of AD patients and contributes to the local inflammatory response triggered by senile plaque. The existence of an inflammatory component in AD is now well known on the basis of epidemiological findings showing a reduced prevalence of the disease upon long-term medication with anti-inflammatory drugs, and evidence from studies of clinical materials that shows an accumulation of activated glial cells, particularly microglia and astrocytes, in the same areas as amyloid plaques. Glial cells maintain brain plasticity and protect the brain for functional recovery from injuries. Dysfunction of glial cells may promote neurodegeneration and, eventually, the retraction of neuronal synapses, which leads to cognitive deficits. The focus of this review is on glial cells and their diversity properties in AD.

Show MeSH
Related in: MedlinePlus