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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

Age-related changes in expression of dynactinP-50 (DynP50) and β-amyloid precursor protein (βAPP). Dynactin-P50 and βAPP were detected by immunofluorescence in tissue sections from hippocampus at the level of the lateral geniculate nucleus from 6 neurologically normal individuals across an age span of 16–80 years. (A) Representative immunofluorescent images from the six individuals; blue represents DAPI staining of cellular DNA, red represents dynactinP-50, green represents βAPP, and yellow represents colocalization of dynactinP-50 and βAPP. Images were digitized at 20× magnification. Scale bar = 20 μm. Quantitation of dynactinP-50 (B) and βAPP (C) immunofluorescence intensity was obtained by thresholding gray-scale images and integrating pixels as described in Materials and Methods section. Values reflect the mean of 6 images per specimen.
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Figure 2: Age-related changes in expression of dynactinP-50 (DynP50) and β-amyloid precursor protein (βAPP). Dynactin-P50 and βAPP were detected by immunofluorescence in tissue sections from hippocampus at the level of the lateral geniculate nucleus from 6 neurologically normal individuals across an age span of 16–80 years. (A) Representative immunofluorescent images from the six individuals; blue represents DAPI staining of cellular DNA, red represents dynactinP-50, green represents βAPP, and yellow represents colocalization of dynactinP-50 and βAPP. Images were digitized at 20× magnification. Scale bar = 20 μm. Quantitation of dynactinP-50 (B) and βAPP (C) immunofluorescence intensity was obtained by thresholding gray-scale images and integrating pixels as described in Materials and Methods section. Values reflect the mean of 6 images per specimen.

Mentions: Due to the elongated morphology of neurons and their unique functions, precise and timely delivery of specific proteins and organelles by motor proteins must be tightly maintained. In particular, retrograde transport of spent proteins or damaged organelles is very important and is predicted to change with age, as oxidative and inflammatory stresses accumulate with the wear and tear of time. To investigate this prediction, we ask a simple question: Are there changes in the expression of the regulatory cargo attachment protein dynactin-p50 and its cargo βAPP with increasing age in the absence of disease? Dynactin-P50 fluorescent intensity (expression) was noticeably elevated with increasing age, from teenage to the eighth decade, in pyramidal neurons in hippocampal tissue sections from neurologically and neuropathologically normal individuals (Figures 2A,B). This age-related increase in dynactin-P50 expression was accompanied by an increase in βAPP expression in neuronal somas and neuronal processes (Figures 2A,C), suggesting that in response to the normal wear and tear of time, βAPP and dynactin expression are increased for membrane repair and transport of cellular entities.


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)

Age-related changes in expression of dynactinP-50 (DynP50) and β-amyloid precursor protein (βAPP). Dynactin-P50 and βAPP were detected by immunofluorescence in tissue sections from hippocampus at the level of the lateral geniculate nucleus from 6 neurologically normal individuals across an age span of 16–80 years. (A) Representative immunofluorescent images from the six individuals; blue represents DAPI staining of cellular DNA, red represents dynactinP-50, green represents βAPP, and yellow represents colocalization of dynactinP-50 and βAPP. Images were digitized at 20× magnification. Scale bar = 20 μm. Quantitation of dynactinP-50 (B) and βAPP (C) immunofluorescence intensity was obtained by thresholding gray-scale images and integrating pixels as described in Materials and Methods section. Values reflect the mean of 6 images per specimen.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: Age-related changes in expression of dynactinP-50 (DynP50) and β-amyloid precursor protein (βAPP). Dynactin-P50 and βAPP were detected by immunofluorescence in tissue sections from hippocampus at the level of the lateral geniculate nucleus from 6 neurologically normal individuals across an age span of 16–80 years. (A) Representative immunofluorescent images from the six individuals; blue represents DAPI staining of cellular DNA, red represents dynactinP-50, green represents βAPP, and yellow represents colocalization of dynactinP-50 and βAPP. Images were digitized at 20× magnification. Scale bar = 20 μm. Quantitation of dynactinP-50 (B) and βAPP (C) immunofluorescence intensity was obtained by thresholding gray-scale images and integrating pixels as described in Materials and Methods section. Values reflect the mean of 6 images per specimen.
Mentions: Due to the elongated morphology of neurons and their unique functions, precise and timely delivery of specific proteins and organelles by motor proteins must be tightly maintained. In particular, retrograde transport of spent proteins or damaged organelles is very important and is predicted to change with age, as oxidative and inflammatory stresses accumulate with the wear and tear of time. To investigate this prediction, we ask a simple question: Are there changes in the expression of the regulatory cargo attachment protein dynactin-p50 and its cargo βAPP with increasing age in the absence of disease? Dynactin-P50 fluorescent intensity (expression) was noticeably elevated with increasing age, from teenage to the eighth decade, in pyramidal neurons in hippocampal tissue sections from neurologically and neuropathologically normal individuals (Figures 2A,B). This age-related increase in dynactin-P50 expression was accompanied by an increase in βAPP expression in neuronal somas and neuronal processes (Figures 2A,C), suggesting that in response to the normal wear and tear of time, βAPP and dynactin expression are increased for membrane repair and transport of cellular entities.

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