The Role of mTOR and Ubiquitin in Plaque and Tangle Formation in Alzheimer's Disease Pathogenesis: A Report of Co‐localization in Two Alzheimer's Autopsy Cases

Abstract

The brains from two patients that died with Alzheimer's disease were examined to determine the role of mTOR and ubiquitin in the pathogenesis of plaque and tangle formation. Conditions of ongoing stress can lead to a failure of normal homeostatic mechanisms, mTOR signaling dysregulation, and accumulation of ubiquitinated protein aggregates. Ubiquitin is known to accumulate in neuritic plaques and neurofibrillary tangles, and we hypothesized that mTOR would co-localize with ubiquitin in neurodegenerative protein aggregates. Formalin-fixed, Paraffin-embeded tissue blocks were obtained from autopsies obtained at a county hospital. Standard H&E and Sevier-Munger stained slides were reviewed, and IHC was performed mTOR and ubiquitin. The slides were double stained with antibodies (conjugated to fluorophores) to mTOR and ubiquitin, and visualized on a fluorescent microscope. Alzheimer's patients showed co-localization of mTOR and ubiquitin within cells associate with both plaques and tangles. We identified plaques and tangles in both patients in the hippocampus consistent with previous neuropathologic diagnoses of Alzheimer's dementia. For the first time, we have demonstrated that mTOR and ubiquitin co-localize to neuritic plaques and neurofibrillary tangles found in Alzheimer's disease. These findings further supports the already existing evidence that the mTOR/autophagy system is likely involved in the pathogenesis of Alzheimer's disease, and perhaps is involved in other neurodegenerative diseases as well. Support or Funding Information None Patient 1 (A) Neuritic plaque with IHC staining of B-amyloid. 436× (B) The neurofibrillary tangles in Patient 1 specimen triple-stained for DAPI (blue), Ubiquitin (red), and mTOR (green). 959× (C) Neurofibrillary tangles with IHC staining for Tau. 436× (D) Neuritic plaque (Patient 1) showing aggregation of ubiquitin (green) and mTOR (red). 959x Patient 2 (A) Neuritic plaque with IHC stain for B-amyloid. 436× (B) A neurofibrillary tangle in Patient 2 double stained for Ubiquitin (red), and mTOR (green). 959× (C) Patient 2 Sevier-Munger stain highlighting tangles. 436× (D) Cells with colocalization of mTOR (red) and ubiquitin (green) in neurons with tangle formation. 959x This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.