Extrusion of misfolded and aggregated proteins – a protective strategy of aging neurons?
Article first published online: 19 JUN 2012
© 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd
European Journal of Neuroscience
Special Issue: EARLY BRAIN REPAIR AND PROTECTION
Volume 35, Issue 12, pages 1938–1950, June 2012
How to Cite
Doehner, J., Genoud, C., Imhof, C., Krstic, D. and Knuesel, I. (2012), Extrusion of misfolded and aggregated proteins – a protective strategy of aging neurons?. European Journal of Neuroscience, 35: 1938–1950. doi: 10.1111/j.1460-9568.2012.08154.x
- Issue published online: 19 JUN 2012
- Article first published online: 19 JUN 2012
- Received 6 February 2012, revised 23 March 2012, accepted 10 April 2012
- Alzheimer’s disease;
- immunoelectron microscopy;
- prenatal infection;
- serial block-face scanning electron microscopy
Cellular senescence is the consequence of repetitive exposures to oxidative stress, perturbed energy homeostasis, accumulation of damaged proteins and lesions in their nucleic acids. Whereas mitotic cells are equipped with efficient cell replacement strategies; postmitotic neurons have - with a few exceptions - no mechanism to substitute dysfunctional cells within a complex neuronal network. Here we propose a potential strategy by which aging neurons contend against abnormal accumulation of damaged/misfolded proteins. The suggested mechanism involves the formation of ‘budding-like’ extrusions and their subsequent clearance by glia. This hypothesis emerged from our previous investigations of the aged hippocampus revealing layer-specific accumulations of Reelin, a glycoprotein with fundamental roles during brain development and adult synaptic plasticity. We showed that Reelin deposits constitute a conserved neuropathological feature of aging, which is significantly accelerated in adult wild-type mice prenatally exposed to a viral-like infection. Here, we employed two- and three-dimensional immunoelectron microscopy to elucidate their morphological properties, localization and origin in immune challenged vs. control mice. In controls, Reelin-positive deposits were dispersed in the neuropil, some being engulfed by glia. In immune challenged mice, however, significantly more Reelin-immunoreactive deposits were associated with neuritic swellings containing mitochondria, vacuoles and cellular debris, pointing to their intracellular origin and suggesting that ‘budding-like’ neuronal extrusions of misfolded proteins and glial clearance may represent a protective strategy to counteract aging-associated impairments in proteosomal/lysosomal degradation. Neurons exposed to chronic neuroinflammation with increased levels of misfolded/damaged proteins, however, may fail to combat intraneuronal protein accumulations, a process probably underlying neuronal dysfunction and degeneration during aging.