Perforin Promotes Amyloid Beta Internalisation in Neurons
Abstract
Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ40 and Aβ42 were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ40 (250 nM) compared with Aβ42 (100 nM). The internalised Aβ40 showed a dot-like pattern of distribution whereas Aβ42 accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ40 and Aβ42 co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ40) and 50 (Aβ42) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ...Continue Reading
References
Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide.
Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease
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