Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system
Amyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.
Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.
Under normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.
Our results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.
- Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system
- Open Access
- Available under Open Access This content is freely available online to anyone, anywhere at any time.
- Online Date
- September 2012
- Online ISSN
- BioMed Central
- Additional Links
- Alzheimer disease
- Amyloid β-protein
- Author Affiliations
- 1. Division of Geriatric Medicine, Department of Clinical and Experimental Medicine, IKE, Faculty of Health Sciences, Linköping University, Linköping, SE-581 85, Sweden
- 2. KI-AlzheimerDisease Research Center, NVS, Novum, Karolinska Institutet, Stockholm, SE-141 57, Sweden
- 3. Division of Pathology, Department of Clinical and Experimental Medicine, IKE, Faculty of Health Science, Linköping University, Linköping, SE-581 85, Sweden
- 4. Departmentof Pathology, Linköping University Hospital, Linköping, SE-581 85, Sweden
- 5. Experimental Pathology, Department of Clinical and Experimental Medicine, IKE, Faculty of Health Science, Linköping University, Linkoping, SE-581 85, Sweden
- 6. Department of Clinical Pathology and Cytology, Karolinska University Hospital, Stockholm, SE-141 86, Huddinge, Sweden