Endocytic pathway

General description

During endocytosis, extracellular material is transported into the cell through internalisation of plasma membrane. The internalisation is mostly mediated though clathrin, initiated by redistribution of membrane proteins into clathrin-coated pits. The internalised vesicle fuses with early endosome, a process regulated by small GTPase Rab5 (Bucci et al., 1992)⁠. During the maturation from early to late endosome, budding events occur, creating a collection of internal vesicles. Late endosome can receive digestive enzyme, fuse with lysosome or fuse with autophagosomes (Nixon, 2005)⁠.

Proper neuronal function requires endocytosis because its polarised shape, therefore, the need to  communicate between synaptic active zones and perikaryon.

References:
  • Bucci, C., Parton, R. G., Mather, I. H., Stunnenberg, H., Simons, K., Hoflack, B., & Zerial, M. (1992). The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell, 70, 715–728. doi:10.1016/0962-8924(92)90043-M
  • Nixon, R. A. (2005). Endosome function and dysfunction in Alzheimer’s disease and other neurodegenerative diseases. In Neurobiology of Aging (Vol. 26, pp. 373–382). doi:10.1016/j.neurobiolaging.2004.09.018
Reactome REACT_19187.1,REACT_27258.1
KEGG Pathways 04144
Involvement in Alzheimer's disease

Altered neuronal endocytosis is one of the earliest changes known to AD (Cataldo et al., 2000)⁠. Endocytosis can accelerates Aβ generation (Grbovic et al., 2003)⁠, as endosome can transport APP to undergo β-cleavage at a more distanced site, and early endosome may contain components of γ- secretase complex (Pasternak et al., 2003)⁠.

At the early stage of AD, the increase of soluble Aβ level is often companioned with enlarged Rab5-positive endosome (Cataldo et al., 2004)⁠. It seems that APP may also exert effect on endosome trafficking (Nixon, 2005)⁠.

References:
  • Cataldo, A. M., Petanceska, S., Terio, N. B., Peterhoff, C. M., Durham, R., Mercken, M., … Nixon, R. A. (2004). Aβ localization in abnormal endosomes: Association with earliest Aβ elevations in AD and Down syndrome. Neurobiology of Aging, 25, 1263–1272. doi:10.1016/j.neurobiolaging.2004.02.027
  • Cataldo, A. M., Peterhoff, C. M., Troncoso, J. C., Gomez-Isla, T., Hyman, B. T., & Nixon, R. A. (2000). Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer’s disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. The American Journal of Pathology, 157, 277–286. doi:S0002-9440(10)64538-5 [pii]
  • Grbovic, O. M., Mathews, P. M., Jiang, Y., Schmidt, S. D., Dinakar, R., Summers-Terio, N. B., … Cataldo, A. M. (2003). Rab5-stimulated up-regulation of the endocytic pathway increases intracellular beta-cleaved amyloid precursor protein carboxyl-terminal fragment levels and Abeta production. The Journal of Biological Chemistry, 278, 31261–31268. doi:10.1074/jbc.M304122200
  • Pasternak, S. H., Bagshaw, R. D., Guiral, M., Zhang, S., Ackerley, C. A., Pak, B. J., … Mahuran, D. J. (2003). Presenilin-1, nicastrin, amyloid precursor protein, and gamma-secretase activity are co-localized in the lysosomal membrane. The Journal of Biological Chemistry, 278, 26687–26694. doi:10.1074/jbc.M212192200\rM212192200 [pii]
Proteins involved
BIN1 BIN1_HUMAN
APOE APOE_HUMAN
PICALM PICAL_HUMAN
CLU CLUS_HUMAN
AP2M1 AP2M1_HUMAN