Paradoxical effects of mutant ubiquitin on A beta plaque formation in an Alzheimer mouse model
NEUROBIOLOGY OF AGING
Authors: Verheijen, Bert M.; Stevens, Jo A. A.; Gentier, Romina J. G.; van't Hekke, Christian D.; van den Hove, Daniel L. A.; Hermes, Denise J. H. P.; Steinbusch, Harry W. M.; Ruijter, Jan M.; Grimm, Marcus O. W.; Haupenthal, Viola J.; Annaert, Wim; Hartmann, Tobias; van Leeuwen, Fred W.
Abstract
Amyloid-beta (Ab) plaques are a prominent pathological hallmark of Alzheimer's disease (AD). They consist of aggregated A beta peptides, which are generated through sequential proteolytic processing of the transmembrane protein amyloid precursor protein (APP) and several A beta-associated factors. Efficient clearance of A beta from the brain is thought to be important to prevent the development and progression of AD. The ubiquitin-proteasome system (UPS) is one of the major pathways for protein breakdown in cells and it has been suggested that impaired UPS-mediated removal of protein aggregates could play an important role in the pathogenesis of AD. To study the effects of an impaired UPS on Ab pathology in vivo, transgenic APP(Swe)/PS1 Delta E9 mice (APPPS1) were crossed with transgenic mice expressing mutant ubiquitin (UBB+1), a protein-based inhibitor of the UPS. Surprisingly, the APPPS1/UBB+1 crossbreed showed a remarkable decrease in Ab plaque load during aging. Further analysis showed that UBB+1 expression transiently restored PS1-NTF expression and g-secretase activity in APPPS1 mice. Concurrently, UBB+1 decreased levels of beta-APP-CTF, which is a g-secretase substrate. Although UBB+1 reduced Ab pathology in APPPS1 mice, it did not improve the behavioral deficits in these animals. (C) 2018 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license.
Mutant ubiquitin and p62 immunoreactivity in cases of combined multiple system atrophy and Alzheimer's disease
ACTA NEUROPATHOLOGICA
Authors: Terni, Beatrice; Rey, Maria Jesus; Boluda, Susana; Torrejon-Escribano, Benjamin; Sabate, M. Pujol; Calopa, Matil; van Leeuwen, Fred W.; Ferrer, Isidro
Abstract
Recent studies have shown the co-existence of alpha-synuclein and phosphorylated tau (pTau) in several neurodegenerative diseases. Here, we report two autopsy cases of combined multiple system atrophy (MSA) and Alzheimer's disease (AD). In both cases, abundant alpha-synuclein-positive glial and neuronal cytoplasmic inclusions were found in the brainstem, amygdala and hippocampal formation. pTau-positive neurofibrillary tangles (NFTs) were widely distributed in case 1 (Braak stage VI) and moderate in case 2 (Braak stage III). Although alpha-synuclein and pTau pathology co-occurred in the hippocampus and entorhinal cortex, only a few neurons showed co-existence of these two proteins. Immunoreactivity for p62, a ubiquitin proteasome system related protein, was found in the majority of NFTs, but in only a small proportion of neuronal alpha-synuclein inclusions. In addition, UBB+1, a mutant form of ubiquitin and a marker for proteasomal dysfunction, was present in the majority of NFTs, whereas co-existence of alpha-synuclein and UBB+1 was found in only a few neurons. These findings indicate that alpha-synuclein and phosphorylated tau co-occur in certain brain regions in cases of combined MSA and AD and that the proteasomal pathways differ between alpha-synuclein- and pTau-bearing neurons.