Preservation of cortical sortilin protein levels in MCI and Alzheimer's disease

Abstract

The nerve growth factor (NGF) precursor protein proNGF is the predominant NGF moiety found in the human neocortex and exhibits pro-apoptotic properties when bound to the p75(NTR) neurotrophin receptor in the presence of sortilin, a Vps10p domain trafficking protein. Recently studies have shown that proNGF levels increase in the cortex of people who died with early stage Alzheimer's disease (AD) or with mild cognitive impairment (MCI), a putative prodromal AD stage. In contrast, cortical levels of the high-affinity, pro-survival NGF receptor TrkA are reduced in AD despite stable levels of p75(NTR). These data suggest a stoichiometric shift in proNGF and its receptors which favors proNGF binding of p75(NTR). Whether cortical levels of sortilin are altered during the progression of AD remains unknown. Therefore, we measured sortilin protein levels in postmortem superior frontal and superior temporal cortical tissues derived from Religious Orders Study subjects clinically diagnosed antemortem with no cognitive impairment (NCI), MCI or AD. No changes in frontal or temporal cortical sortilin protein levels occurred across the clinical groups. There was no association between sortilin levels and antemortem cognitive test scores. However, there was a positive association between temporal cortex sortilin levels and severity of neuropathology by Braak and NIA-Reagan diagnoses. The stability of cortical sortilin levels in the face of stable p75(NTR), increased proNGF, and reduced TrkA levels may favor pro-apoptotic proNGF:p75(NTR):sortilin trimeric interactions within the cortex during the earliest stages of AD. These findings are relevant to the development of NGF drug therapy for the treatment of dementia.

Figure 1

Cortical sortilin protein levels are stable during the progression of AD. A. Western blot shows strong sortilin immunoreactivity antibody in the cortex of a wild type (sortilin +/+) mouse, intermediate levels in a sortilin heterozygous mouse (+/−), and no reactivity in the cortex of a sortilin knockout mouse (−/−). B and C. Representative western blots and box plots showing sortilin and synaptotagmin immunoreactivity in the superior frontal (left) and superior temporal (right) cortex of subjects who died with a clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or Alzheimer’s disease (AD). Synaptotagmin was used as the loading control for normalizing sortilin signals [10]. Box plot shows distribution of normalized mean values of cortical sortilin immunoractivity among the NCI, MCI and AD subjects examined.