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Synapses and dendritic spines as pathogenic targets in Alzheimer's disease.

Yu W, Lu B - Neural Plast. (2012)

Bottom Line: Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment.Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease.It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

ABSTRACT
Synapses are sites of cell-cell contacts that transmit electrical or chemical signals in the brain. Dendritic spines are protrusions on dendritic shaft where excitatory synapses are located. Synapses and dendritic spines are dynamic structures whose plasticity is thought to underlie learning and memory. No wonder neurobiologists are intensively studying mechanisms governing the structural and functional plasticity of synapses and dendritic spines in an effort to understand and eventually treat neurological disorders manifesting learning and memory deficits. One of the best-studied brain disorders that prominently feature synaptic and dendritic spine pathology is Alzheimer's disease (AD). Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment. Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease. It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.

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Related in: MedlinePlus

A diagram depicting a potential role of glia in mediating the synaptic toxicity of Aβ. Aβ oligomers presumably secreted from the presynaptic neuron could bind to its putative receptor on the postsynaptic cell, and this could then initiate a signaling cascade leading to activation kinases such as MARK, which then acts on tau, PSD-95, and possibly other synaptic substrates to affect AMPAR removal from the synaptic surface, leading to synapse and spine loss. Alternatively, Aβ could act on glial cells near neuronal synapses, which then release factors such as cytokines to activate signaling molecules such as MARK and cause synapse and spine loss. These two mechanisms are not mutually exclusive and could in fact occur simultaneously to mediate Aβ toxicity.
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fig2: A diagram depicting a potential role of glia in mediating the synaptic toxicity of Aβ. Aβ oligomers presumably secreted from the presynaptic neuron could bind to its putative receptor on the postsynaptic cell, and this could then initiate a signaling cascade leading to activation kinases such as MARK, which then acts on tau, PSD-95, and possibly other synaptic substrates to affect AMPAR removal from the synaptic surface, leading to synapse and spine loss. Alternatively, Aβ could act on glial cells near neuronal synapses, which then release factors such as cytokines to activate signaling molecules such as MARK and cause synapse and spine loss. These two mechanisms are not mutually exclusive and could in fact occur simultaneously to mediate Aβ toxicity.

Mentions: Despite the large amount of literature documenting a detrimental role for microglia and astrocyte activation in the disease process, these cells are important for neuronal heath during development and later in adult life. For example, microglia are proposed to play a surveillance role by constantly monitoring and sensing synaptic health [92], and, in addition to the critical roles, astrocytes play in synapse formation as mentioned earlier, and these cells can also control extracellular glutamate levels, remove excess extracellular K+, release gliotransmitters, store glucose and transform it into lactate as energy source of neurons, and scavenge ROS to protect against oxidative damages [88]. Given these essential roles of glia to neuronal function and health, it is possible that damaging of glial cells by Aβ may have equally harmful effect on the neurons eventually. In fact, there is evidence that glial cells can release ROS upon Aβ exposure [93], and glial-released cytokines may even trigger a signaling process that promotes tau hyperphosphorylation [94]. Thus, a possible role of dysfunction glial cells in AD pathogenesis should be considered, especially in the early stages of the disease process (Figure 2).


Synapses and dendritic spines as pathogenic targets in Alzheimer's disease.

Yu W, Lu B - Neural Plast. (2012)

A diagram depicting a potential role of glia in mediating the synaptic toxicity of Aβ. Aβ oligomers presumably secreted from the presynaptic neuron could bind to its putative receptor on the postsynaptic cell, and this could then initiate a signaling cascade leading to activation kinases such as MARK, which then acts on tau, PSD-95, and possibly other synaptic substrates to affect AMPAR removal from the synaptic surface, leading to synapse and spine loss. Alternatively, Aβ could act on glial cells near neuronal synapses, which then release factors such as cytokines to activate signaling molecules such as MARK and cause synapse and spine loss. These two mechanisms are not mutually exclusive and could in fact occur simultaneously to mediate Aβ toxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3306944&req=5

fig2: A diagram depicting a potential role of glia in mediating the synaptic toxicity of Aβ. Aβ oligomers presumably secreted from the presynaptic neuron could bind to its putative receptor on the postsynaptic cell, and this could then initiate a signaling cascade leading to activation kinases such as MARK, which then acts on tau, PSD-95, and possibly other synaptic substrates to affect AMPAR removal from the synaptic surface, leading to synapse and spine loss. Alternatively, Aβ could act on glial cells near neuronal synapses, which then release factors such as cytokines to activate signaling molecules such as MARK and cause synapse and spine loss. These two mechanisms are not mutually exclusive and could in fact occur simultaneously to mediate Aβ toxicity.
Mentions: Despite the large amount of literature documenting a detrimental role for microglia and astrocyte activation in the disease process, these cells are important for neuronal heath during development and later in adult life. For example, microglia are proposed to play a surveillance role by constantly monitoring and sensing synaptic health [92], and, in addition to the critical roles, astrocytes play in synapse formation as mentioned earlier, and these cells can also control extracellular glutamate levels, remove excess extracellular K+, release gliotransmitters, store glucose and transform it into lactate as energy source of neurons, and scavenge ROS to protect against oxidative damages [88]. Given these essential roles of glia to neuronal function and health, it is possible that damaging of glial cells by Aβ may have equally harmful effect on the neurons eventually. In fact, there is evidence that glial cells can release ROS upon Aβ exposure [93], and glial-released cytokines may even trigger a signaling process that promotes tau hyperphosphorylation [94]. Thus, a possible role of dysfunction glial cells in AD pathogenesis should be considered, especially in the early stages of the disease process (Figure 2).

Bottom Line: Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment.Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease.It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

ABSTRACT
Synapses are sites of cell-cell contacts that transmit electrical or chemical signals in the brain. Dendritic spines are protrusions on dendritic shaft where excitatory synapses are located. Synapses and dendritic spines are dynamic structures whose plasticity is thought to underlie learning and memory. No wonder neurobiologists are intensively studying mechanisms governing the structural and functional plasticity of synapses and dendritic spines in an effort to understand and eventually treat neurological disorders manifesting learning and memory deficits. One of the best-studied brain disorders that prominently feature synaptic and dendritic spine pathology is Alzheimer's disease (AD). Recent studies have revealed molecular mechanisms underlying the synapse and spine pathology in AD, including a role for mislocalized tau in the postsynaptic compartment. Synaptic and dendritic spine pathology is also observed in other neurodegenerative disease. It is possible that some common pathogenic mechanisms may underlie the synaptic and dendritic spine pathology in neurodegenerative diseases.

Show MeSH
Related in: MedlinePlus