Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Abstract

BackgroundAmyloid 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.MethodsUsing 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.ResultsUnder 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.ConclusionOur 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.

Clearance systems in the brain—implications for Alzheimer disease

“…The most common soluble monomeric isoforms of Aβ are Aβ 1–40 (<80%), Aβ 1–38 (<20%) and Aβ 1–42 (10%). 105 Aβ 1–40 is prone to be deposited in the vasculature, as seen in CAA. 15,106 Aβ 1–38 is less likely to aggregate in either the vasculature or the brain than the other isoforms.…”

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-β-induced Neuronal Death

“…Reports suggest that A␤ from the medium is internalized by the PC12 cells, enters their nuclei (57), and leads to death of PC12 cells (58). Studies also reveal that A␤ enters neurons and is present in their lysosomal system (59), whereas inhibition of its engulfment reduces death of neurons (60). A␤ immunoreactivity has also been found in degenerating neurons in transgenic mice and AD brains (61,62).…”

One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

“…Several studies have recognised the endosomal/lysosomal pathway as an important regulator of APP processing. Lysosomal involvement in Ab generation is further discernible as these organelles contain both APP as substrate and b-and c-secretases as its processing enzymes [94]. Endosomes are involved in Ab production from APP and mediate the uptake of Ab and soluble APP.…”