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

Orwa Aboud,W Sue T Griffin,Robert E Mrak,Paul A Parcon,K Mark Dewall,Ling Liu

doi:10.3389/fncel.2015.00103

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.

Highlights

Fast-axonal transport is an essential part of normal neuronal function (Paschal and Vallee, 1987; Brady, 1991), and transport failures manifest as a dying-back of axons from the synapse to the neuronal soma, a phenomena that occurs prior to the neuronal loss characteristic of Alzheimer’s disease (AD) (Kanaan et al, 2013)
ΒAPP and Dynactin-P50 Expression is Diminished in Alzheimer Hippocampus In order to assess the effect of AD on the amount of β amyloid precursor protein (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)
Normal Aging We focused on βAPP because it is the acute phase response protein in neurons (Barger et al, 2008) and is of particular importance in Alzheimer pathogenesis; and on dynein, in particular dynactin-P50, the cargo-binding protein of dynein, because βAPP is a prominent cargo for retrograde transport (Gunawardena et al, 2013)

Summary

Introduction

Fast-axonal transport is an essential part of normal neuronal function (Paschal and Vallee, 1987; Brady, 1991), and transport failures manifest as a dying-back of axons from the synapse to the neuronal soma, a phenomena that occurs prior to the neuronal loss characteristic of Alzheimer’s disease (AD) (Kanaan et al, 2013). The active dynein complex is important in alignment of microtubules and is, at least partially, responsible for the growth of microtubules into the growth cone of axons (Ahmad et al, 2006). These functions suggest that dynein is needed for neuronal survival, especially for the survival of those neurons with long axons that function to connect CNS neuronal somas with distant targets in the periphery (Ebneth et al, 1998; Heerssen et al, 2004). Dynein-mediated axonal transport depends on interactions between neurotrophic factors, their receptors, and the dynein complex. Decreased brain-derived neurotropic factor (BDNF) is associated with decreased retrograde transport (Heerssen et al, 2004)

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