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DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer's disease

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ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by senile plaques, neurofibrillary tangles, synaptic disruption, and neuronal loss. Several studies have demonstrated decreases of docosahexaenoic acid-containing phosphatidylcholines (DHA-PCs) in the AD brain. In this study, we used matrix-assisted laser desorption/ionization imaging mass spectrometry in postmortem AD brain to show that PC molecular species containing stearate and DHA, namely PC(18:0/22:6), was selectively depleted in the gray matter of patients with AD. Moreover, in the brain regions with marked amyloid β (Aβ) deposition, the magnitude of the PC(18:0/22:6) reduction significantly correlated with disease duration. Furthermore, at the molecular level, this depletion was associated with reduced levels of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. Interestingly, this reduction in PC(18:0/22:6) levels did not correlate with the degrees of Aβ deposition and neuronal loss in AD. The analysis of the correlations of key factors and disease duration showed that their effects on the disease time course were arranged in order as Aβ deposition, presynaptic disruption, postsynaptic disruption coupled with PC(18:0/22:6) reduction, and neuronal loss.

No MeSH data available.


Hypothetical cascade in AD progression.A PC(18:0/22:6) reduction parallels postsynaptic disruption when plotted against disease duration, but it does not parallel Aβ deposition, neuronal loss, and presynaptic disruption. It is generally accepted that Aβ deposition becomes abnormal early and before the appearance of clinical symptom, and the abnormal brain morphology resulting from neuronal loss happens late relative to neuronal dysfunction31. Because the loss of synaptophysin was not correlated with the disease durations of the patients in this study, presynaptic disruption may occur earlier than postsynaptic disruption. The solid lines show the results of this study, and the broken lines show our speculation.
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f7: Hypothetical cascade in AD progression.A PC(18:0/22:6) reduction parallels postsynaptic disruption when plotted against disease duration, but it does not parallel Aβ deposition, neuronal loss, and presynaptic disruption. It is generally accepted that Aβ deposition becomes abnormal early and before the appearance of clinical symptom, and the abnormal brain morphology resulting from neuronal loss happens late relative to neuronal dysfunction31. Because the loss of synaptophysin was not correlated with the disease durations of the patients in this study, presynaptic disruption may occur earlier than postsynaptic disruption. The solid lines show the results of this study, and the broken lines show our speculation.

Mentions: To examine the association with neurodegeneration in AD, we evaluated the possible relationship between the decrease in PC(18:0/22:6) and the loss of NeuN-positive cells (Fig. 5a). The density of NeuN-positive cells in AD brain did not correlate with a decrease in PC(18:0/22:6), but the density of the NeuN-positive cells negatively correlated with disease duration. These results indicated that the PC(18:0/22:6) reduction was not associated with neuronal loss. We next evaluated the relationship between the decrease in PC(18:0/22:6) and the loss of synaptic proteins (Fig. 5b). The postsynaptic protein PSD-95 was strongly correlated with PC(18:0/22:6) and disease duration (Fig. 5c and d). Similarly, the postsynaptic protein NR2B was strongly correlated with PC(18:0/22:6) and disease duration (Supplementary Fig. 1). However, the presynaptic protein synaptophysin did not correlate with PC(18:0/22:6) and disease duration, even though its levels were decreased in the AD brains. Although other presynaptic protein Munc-18-1 was correlated with PC(18:0/22:6), it did not correlate with disease duration (Supplementary Fig. 1). From these results, we hypothesized that the PC(18:0/22:6) was decreased at the clinical disease stage of AD and the reduction was more tightly associated with the postsynaptic disruptions than with the presynaptic disruptions (Fig. 7).


DHA-PC and PSD-95 decrease after loss of synaptophysin and before neuronal loss in patients with Alzheimer's disease
Hypothetical cascade in AD progression.A PC(18:0/22:6) reduction parallels postsynaptic disruption when plotted against disease duration, but it does not parallel Aβ deposition, neuronal loss, and presynaptic disruption. It is generally accepted that Aβ deposition becomes abnormal early and before the appearance of clinical symptom, and the abnormal brain morphology resulting from neuronal loss happens late relative to neuronal dysfunction31. Because the loss of synaptophysin was not correlated with the disease durations of the patients in this study, presynaptic disruption may occur earlier than postsynaptic disruption. The solid lines show the results of this study, and the broken lines show our speculation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5382699&req=5

f7: Hypothetical cascade in AD progression.A PC(18:0/22:6) reduction parallels postsynaptic disruption when plotted against disease duration, but it does not parallel Aβ deposition, neuronal loss, and presynaptic disruption. It is generally accepted that Aβ deposition becomes abnormal early and before the appearance of clinical symptom, and the abnormal brain morphology resulting from neuronal loss happens late relative to neuronal dysfunction31. Because the loss of synaptophysin was not correlated with the disease durations of the patients in this study, presynaptic disruption may occur earlier than postsynaptic disruption. The solid lines show the results of this study, and the broken lines show our speculation.
Mentions: To examine the association with neurodegeneration in AD, we evaluated the possible relationship between the decrease in PC(18:0/22:6) and the loss of NeuN-positive cells (Fig. 5a). The density of NeuN-positive cells in AD brain did not correlate with a decrease in PC(18:0/22:6), but the density of the NeuN-positive cells negatively correlated with disease duration. These results indicated that the PC(18:0/22:6) reduction was not associated with neuronal loss. We next evaluated the relationship between the decrease in PC(18:0/22:6) and the loss of synaptic proteins (Fig. 5b). The postsynaptic protein PSD-95 was strongly correlated with PC(18:0/22:6) and disease duration (Fig. 5c and d). Similarly, the postsynaptic protein NR2B was strongly correlated with PC(18:0/22:6) and disease duration (Supplementary Fig. 1). However, the presynaptic protein synaptophysin did not correlate with PC(18:0/22:6) and disease duration, even though its levels were decreased in the AD brains. Although other presynaptic protein Munc-18-1 was correlated with PC(18:0/22:6), it did not correlate with disease duration (Supplementary Fig. 1). From these results, we hypothesized that the PC(18:0/22:6) was decreased at the clinical disease stage of AD and the reduction was more tightly associated with the postsynaptic disruptions than with the presynaptic disruptions (Fig. 7).

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer's disease (AD) is a progressive neurodegenerative disease that is characterized by senile plaques, neurofibrillary tangles, synaptic disruption, and neuronal loss. Several studies have demonstrated decreases of docosahexaenoic acid-containing phosphatidylcholines (DHA-PCs) in the AD brain. In this study, we used matrix-assisted laser desorption/ionization imaging mass spectrometry in postmortem AD brain to show that PC molecular species containing stearate and DHA, namely PC(18:0/22:6), was selectively depleted in the gray matter of patients with AD. Moreover, in the brain regions with marked amyloid β (Aβ) deposition, the magnitude of the PC(18:0/22:6) reduction significantly correlated with disease duration. Furthermore, at the molecular level, this depletion was associated with reduced levels of the postsynaptic protein PSD-95 but not the presynaptic protein synaptophysin. Interestingly, this reduction in PC(18:0/22:6) levels did not correlate with the degrees of Aβ deposition and neuronal loss in AD. The analysis of the correlations of key factors and disease duration showed that their effects on the disease time course were arranged in order as Aβ deposition, presynaptic disruption, postsynaptic disruption coupled with PC(18:0/22:6) reduction, and neuronal loss.

No MeSH data available.