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Aging, Alzheimer's, and APOE genotype influence the expression and neuronal distribution patterns of microtubule motor protein dynactin-P50.

Aboud O, Parcon PA, DeWall KM, Liu L, Mrak RE, Griffin WS - Front Cell Neurosci (2015)

Bottom Line: In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced.It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins.We conclude that even in disease the ε3 allele is neuroprotective.

View Article: PubMed Central - PubMed

Affiliation: Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA.

ABSTRACT
Reports from neural cell cultures and experimental animal studies provide evidence of age- and disease-related changes in retrograde transport of spent or misfolded proteins destined for degradation or recycling. However, few studies address these issues in human brain from those who either age without dementia and overt neuropathology, or succumb to Alzheimer's; especially as such propensity may be influenced by APOE genotype. We studied the expression and distribution of the dynein subunit dynactin-P50, the β amyloid precursor protein (βAPP), and hyperphosphorylated tau (P-tau) in tissues and tissue sections of brains from non-demented, neuropathology-free patients and from Alzheimer patients, with either APOE ε3,3 or APOE ε4,4. We found that advanced age in patients without dementia or neuropathological change was associated with coordinated increases in dynactin-P50 and βAPP in neurons in pyramidal layers of the hippocampus. In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced. Furthermore, the dynactin-P50 and βAPP that was present was located primarily in dystrophic neurites in Aβ plaques. Tissues from Alzheimer patients with APOE ε3,3 had less P-tau, more βAPP, dynactin-P50, and synaptophysin than did tissues from Alzheimer patients carrying APOE ε4,4. It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins. The buildup of proteins slated for repair, synaptic viability, transport, and re-cycling in neuron soma and dystrophic neurites suggest a loss of this coordination in Alzheimer neurons. Inheritance of APOE ε3,3 rather than APOE ε4,4, is associated with neuronal resilience, suggestive of better repair capabilities, more synapses, more efficient transport, and less hyperphosphorylation of tau. We conclude that even in disease the ε3 allele is neuroprotective.

No MeSH data available.


Related in: MedlinePlus

βAPP levels are reduced in Alzheimer's (AD), and dynactin-P50 (DynP50) and βAPP localization is disrupted. Dynactin-P50 (green) and βAPP (red) were detected by immunofluorescence in tissue sections from hippocampus. (A) Total APP intensity is decreased in AD cases. Blue represents DAPI staining of cellular DNA. Images were digitized at 40× magnification. Scale bar = 10 μm. (B) Overall βAPP fluorescence intensity is diminished in AD compared to neurologically normal controls (AMC). Significance determined by Wilcoxon-Mann-Whitney Rank Sum Test, with *denoting p ≤ 0.05. Data reported as group mean with error bars denoting SEM.
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Figure 4: βAPP levels are reduced in Alzheimer's (AD), and dynactin-P50 (DynP50) and βAPP localization is disrupted. Dynactin-P50 (green) and βAPP (red) were detected by immunofluorescence in tissue sections from hippocampus. (A) Total APP intensity is decreased in AD cases. Blue represents DAPI staining of cellular DNA. Images were digitized at 40× magnification. Scale bar = 10 μm. (B) Overall βAPP fluorescence intensity is diminished in AD compared to neurologically normal controls (AMC). Significance determined by Wilcoxon-Mann-Whitney Rank Sum Test, with *denoting p ≤ 0.05. Data reported as group mean with error bars denoting SEM.

Mentions: In order to assess the effect of AD on the amount of βAPP and dynactin-p50 in the neurons of those with Alzheimer's disease, separate from the effect of normal aging, we selected cases with Alzheimer's disease, and compared them to control individuals that matched them closely in age (AMCs were within 1 year of their AD counterparts, with the total age range for both groups between 69 and 80). We found that there was a dramatic decrease in dynactin-P50 expression in analogous neurons in Alzheimer patients (Figures 3A,B). This decrease is suggestive of the idea that in AD, neurons are unable to transport proteins to the soma for degradation and recycling, perhaps accounting, at least in part, for the deleterious downstream consequences of a build-up of misfolded proteins and potentially-neurotoxic aggregates. The decrease in dynactin-P50 expression in neurons in tissue from Alzheimer patients, compared to that in tissue from age-matched neurologically normal individuals, was accompanied by a similarly marked decrease in neuronal βAPP (Figures 4A,B) and in βAPP mRNA, as we previously reported (Barger et al., 2008).


Aging, Alzheimer's, and APOE genotype influence the expression and neuronal distribution patterns of microtubule motor protein dynactin-P50.

Aboud O, Parcon PA, DeWall KM, Liu L, Mrak RE, Griffin WS - Front Cell Neurosci (2015)

βAPP levels are reduced in Alzheimer's (AD), and dynactin-P50 (DynP50) and βAPP localization is disrupted. Dynactin-P50 (green) and βAPP (red) were detected by immunofluorescence in tissue sections from hippocampus. (A) Total APP intensity is decreased in AD cases. Blue represents DAPI staining of cellular DNA. Images were digitized at 40× magnification. Scale bar = 10 μm. (B) Overall βAPP fluorescence intensity is diminished in AD compared to neurologically normal controls (AMC). Significance determined by Wilcoxon-Mann-Whitney Rank Sum Test, with *denoting p ≤ 0.05. Data reported as group mean with error bars denoting SEM.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4373372&req=5

Figure 4: βAPP levels are reduced in Alzheimer's (AD), and dynactin-P50 (DynP50) and βAPP localization is disrupted. Dynactin-P50 (green) and βAPP (red) were detected by immunofluorescence in tissue sections from hippocampus. (A) Total APP intensity is decreased in AD cases. Blue represents DAPI staining of cellular DNA. Images were digitized at 40× magnification. Scale bar = 10 μm. (B) Overall βAPP fluorescence intensity is diminished in AD compared to neurologically normal controls (AMC). Significance determined by Wilcoxon-Mann-Whitney Rank Sum Test, with *denoting p ≤ 0.05. Data reported as group mean with error bars denoting SEM.
Mentions: In order to assess the effect of AD on the amount of βAPP and dynactin-p50 in the neurons of those with Alzheimer's disease, separate from the effect of normal aging, we selected cases with Alzheimer's disease, and compared them to control individuals that matched them closely in age (AMCs were within 1 year of their AD counterparts, with the total age range for both groups between 69 and 80). We found that there was a dramatic decrease in dynactin-P50 expression in analogous neurons in Alzheimer patients (Figures 3A,B). This decrease is suggestive of the idea that in AD, neurons are unable to transport proteins to the soma for degradation and recycling, perhaps accounting, at least in part, for the deleterious downstream consequences of a build-up of misfolded proteins and potentially-neurotoxic aggregates. The decrease in dynactin-P50 expression in neurons in tissue from Alzheimer patients, compared to that in tissue from age-matched neurologically normal individuals, was accompanied by a similarly marked decrease in neuronal βAPP (Figures 4A,B) and in βAPP mRNA, as we previously reported (Barger et al., 2008).

Bottom Line: In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced.It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins.We conclude that even in disease the ε3 allele is neuroprotective.

View Article: PubMed Central - PubMed

Affiliation: Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, AR, USA.

ABSTRACT
Reports from neural cell cultures and experimental animal studies provide evidence of age- and disease-related changes in retrograde transport of spent or misfolded proteins destined for degradation or recycling. However, few studies address these issues in human brain from those who either age without dementia and overt neuropathology, or succumb to Alzheimer's; especially as such propensity may be influenced by APOE genotype. We studied the expression and distribution of the dynein subunit dynactin-P50, the β amyloid precursor protein (βAPP), and hyperphosphorylated tau (P-tau) in tissues and tissue sections of brains from non-demented, neuropathology-free patients and from Alzheimer patients, with either APOE ε3,3 or APOE ε4,4. We found that advanced age in patients without dementia or neuropathological change was associated with coordinated increases in dynactin-P50 and βAPP in neurons in pyramidal layers of the hippocampus. In contrast, in Alzheimer's, βAPP and dynactin were significantly reduced. Furthermore, the dynactin-P50 and βAPP that was present was located primarily in dystrophic neurites in Aβ plaques. Tissues from Alzheimer patients with APOE ε3,3 had less P-tau, more βAPP, dynactin-P50, and synaptophysin than did tissues from Alzheimer patients carrying APOE ε4,4. It is logical to conclude, then, that as neurons age successfully, there is coordination between retrograde delivery and maintenance and repair, as well as between retrograde delivery and degradation and/or recycling of spent proteins. The buildup of proteins slated for repair, synaptic viability, transport, and re-cycling in neuron soma and dystrophic neurites suggest a loss of this coordination in Alzheimer neurons. Inheritance of APOE ε3,3 rather than APOE ε4,4, is associated with neuronal resilience, suggestive of better repair capabilities, more synapses, more efficient transport, and less hyperphosphorylation of tau. We conclude that even in disease the ε3 allele is neuroprotective.

No MeSH data available.


Related in: MedlinePlus