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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

Dynactin-P50 (DynP50), βAPP, and hyperphosphorylated tau in neurofibrillary tangles (NFT) localization in AD and neurologically normal controls (AMC). (A) Dynactin-P50 (red), βAPP (green), and NFT (blue) were detected by immunofluorescence in hippocampal tissue of AD and neurologically normal individuals (AMC). In AMC (top row), note the absence of neurofibrillary tangles, and increased dynactin-P50 and βAPP compared to AD (middle and bottom rows). Further, DynP50 and βAPP appear brighter in somas of AMC vs. somas of AD without NFTs (white arrows). Dynactin-P50, APP, and NFT immunoreactivity was observed in anuclear bulbous neurites (yellow arrows). AD somas containing NFTs showed the highest immunoreactivity in AD for dynactin-P50, and βAPP, implying possible aggregation of all three antigens (red arrows). (B) Duolink proximity ligation assay (PLA) detects immunogens within 40 nm distance in tissue sections. Image shows neuritic plaque enriched with dynactin-P50 and P-tau in close proximity.
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Figure 5: Dynactin-P50 (DynP50), βAPP, and hyperphosphorylated tau in neurofibrillary tangles (NFT) localization in AD and neurologically normal controls (AMC). (A) Dynactin-P50 (red), βAPP (green), and NFT (blue) were detected by immunofluorescence in hippocampal tissue of AD and neurologically normal individuals (AMC). In AMC (top row), note the absence of neurofibrillary tangles, and increased dynactin-P50 and βAPP compared to AD (middle and bottom rows). Further, DynP50 and βAPP appear brighter in somas of AMC vs. somas of AD without NFTs (white arrows). Dynactin-P50, APP, and NFT immunoreactivity was observed in anuclear bulbous neurites (yellow arrows). AD somas containing NFTs showed the highest immunoreactivity in AD for dynactin-P50, and βAPP, implying possible aggregation of all three antigens (red arrows). (B) Duolink proximity ligation assay (PLA) detects immunogens within 40 nm distance in tissue sections. Image shows neuritic plaque enriched with dynactin-P50 and P-tau in close proximity.

Mentions: In neurologically normal individuals, the increased expression of dynactin-P50 and βAPP associated with advancing age was apparent in the soma and in the axon hillock of both dentate and pyramidal neurons (Figure 5, 1st row). In contrast, in Alzheimer tissue from analogous regions of hippocampus, the expression of dynactin-P50 and βAPP was dramatically reduced in dentate and pyramidal neurons (Figure 5, 2nd and 3rd row). Moreover, in dynactin-P50 and βAPP-immunoreactive neurons that also contained neurofibrillary tangles, there was an apparent preferential redistribution of all three antigens from neuronal somas to neuritic bulbous terminals (Figure 5, neuron soma, white arrows; anuclear neurites, yellow arrows). Large tangle-bearing pyramidal neurons were also noted to contain both βAPP and dynactin-P50. In fact, P-tau immunoreactive tangles, βAPP, and dynactin-P50 appear to be trapped in both soma and neurites (Figure 5, red arrows), which may be due, at least in part, to disruption of the entire (anterograde and retrograde) microtubule motor system, as might be inferred from previous studies demonstrating that endosomal transport and processing are disrupted in Down's syndrome and in Alzheimer's disease (Cataldo et al., 1996). To determine proximity of P-tau and dynactin-p50, we probed tissue with the Duolink Proximity Ligation Assay (PLA). This assay produces a fluorescent signal if two immunogens are within 40 nm distance by using complementary DNA strands on antibody probes with subsequent ligation and detection. In this way, we showed that dynactin-P50 and P-tau are indeed located within 40 nm of each other in neuritic plaques in AD (Figure 5B), strongly suggesting aggregation.


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)

Dynactin-P50 (DynP50), βAPP, and hyperphosphorylated tau in neurofibrillary tangles (NFT) localization in AD and neurologically normal controls (AMC). (A) Dynactin-P50 (red), βAPP (green), and NFT (blue) were detected by immunofluorescence in hippocampal tissue of AD and neurologically normal individuals (AMC). In AMC (top row), note the absence of neurofibrillary tangles, and increased dynactin-P50 and βAPP compared to AD (middle and bottom rows). Further, DynP50 and βAPP appear brighter in somas of AMC vs. somas of AD without NFTs (white arrows). Dynactin-P50, APP, and NFT immunoreactivity was observed in anuclear bulbous neurites (yellow arrows). AD somas containing NFTs showed the highest immunoreactivity in AD for dynactin-P50, and βAPP, implying possible aggregation of all three antigens (red arrows). (B) Duolink proximity ligation assay (PLA) detects immunogens within 40 nm distance in tissue sections. Image shows neuritic plaque enriched with dynactin-P50 and P-tau in close proximity.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4373372&req=5

Figure 5: Dynactin-P50 (DynP50), βAPP, and hyperphosphorylated tau in neurofibrillary tangles (NFT) localization in AD and neurologically normal controls (AMC). (A) Dynactin-P50 (red), βAPP (green), and NFT (blue) were detected by immunofluorescence in hippocampal tissue of AD and neurologically normal individuals (AMC). In AMC (top row), note the absence of neurofibrillary tangles, and increased dynactin-P50 and βAPP compared to AD (middle and bottom rows). Further, DynP50 and βAPP appear brighter in somas of AMC vs. somas of AD without NFTs (white arrows). Dynactin-P50, APP, and NFT immunoreactivity was observed in anuclear bulbous neurites (yellow arrows). AD somas containing NFTs showed the highest immunoreactivity in AD for dynactin-P50, and βAPP, implying possible aggregation of all three antigens (red arrows). (B) Duolink proximity ligation assay (PLA) detects immunogens within 40 nm distance in tissue sections. Image shows neuritic plaque enriched with dynactin-P50 and P-tau in close proximity.
Mentions: In neurologically normal individuals, the increased expression of dynactin-P50 and βAPP associated with advancing age was apparent in the soma and in the axon hillock of both dentate and pyramidal neurons (Figure 5, 1st row). In contrast, in Alzheimer tissue from analogous regions of hippocampus, the expression of dynactin-P50 and βAPP was dramatically reduced in dentate and pyramidal neurons (Figure 5, 2nd and 3rd row). Moreover, in dynactin-P50 and βAPP-immunoreactive neurons that also contained neurofibrillary tangles, there was an apparent preferential redistribution of all three antigens from neuronal somas to neuritic bulbous terminals (Figure 5, neuron soma, white arrows; anuclear neurites, yellow arrows). Large tangle-bearing pyramidal neurons were also noted to contain both βAPP and dynactin-P50. In fact, P-tau immunoreactive tangles, βAPP, and dynactin-P50 appear to be trapped in both soma and neurites (Figure 5, red arrows), which may be due, at least in part, to disruption of the entire (anterograde and retrograde) microtubule motor system, as might be inferred from previous studies demonstrating that endosomal transport and processing are disrupted in Down's syndrome and in Alzheimer's disease (Cataldo et al., 1996). To determine proximity of P-tau and dynactin-p50, we probed tissue with the Duolink Proximity Ligation Assay (PLA). This assay produces a fluorescent signal if two immunogens are within 40 nm distance by using complementary DNA strands on antibody probes with subsequent ligation and detection. In this way, we showed that dynactin-P50 and P-tau are indeed located within 40 nm of each other in neuritic plaques in AD (Figure 5B), strongly suggesting aggregation.

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