ReviewEndosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases
Section snippets
The endocytic pathway
During endocytosis, extracellular material and plasma membrane are internalized and subsequently trafficked through a series of vesicular compartments (Fig. 1). This process, discussed only briefly here, is the subject of many excellent recent reviews [4], [50], [110], [117]. The internalization into vesicles is most often mediated by clathrin, but this can also occur via highly specialized vesicles, the caveolae, or by macropinocytosis, a non-specific bulk phagocytic-like process.
Genetics of endosome dysfunction and AD-like neuropathology in disparate neurodegenerative disorders
Despite their different genetic origins, age of onset, clinical symptoms, and neuropathology, AD, Down syndrome, and Neimann-Pick type C share in common a constellation of pathologic features [79]. This pathology includes not only neurofibrillary tangle formation, increased amyloidogenic APP processing, and neurodegeneration [2], [30], [44], [106], [137] but also the very early development of endosome abnormalities [44], which are influenced by genes that also modify AD onset and neuropathology.
Endocytosis in neurons
Considering the importance of endocytosis to neurons is instructive in understanding how endosome dysfunction may contribute to neurodegeneration, not only in AD, but also in other neurodegenerative diseases. Neurons have extensive and specialized needs for endocytosis, arising from not only their complex requirements for signal transduction but also from their extreme polar shape, which necessarily places the regions most active in signal transduction and inter-cellular communication at
Endosome dysfunction and neurodegeneration
In view of the endosome's importance as an integrator of inter-cellular communication, signaling, and metabolism within the cell, it is easily imagined how even subtle forms of endocytic dysfunction could adversely affect brain function and promote neurodegeneration. Because the window of opportunity for receptors to signal during endocytosis is determined by their rates of degradation, alterations in the balance of proteases in early endosomes as seen in AD, DS, and NPC or in the sorting of
Conclusion
The foregoing studies amply demonstrate that endosomes are major targets of genetic and non-genetic pathogenic factors in a substantial number of neurodegenerative diseases. The dual roles that some endosome-associated proteins have in regulating both endosome function and cell survival/cell death decisions may, in part, explain this connection. Further studies in these diseases to define the specific endosomal compartments involved and the nature of the defects could help to account for
Acknowledgements
I am grateful to Laurie Goldberg for assistance in manuscript preparation and to Corrinne Peterhoff for assistance with graphics. Work from this laboratory has been supported by grants from the National Institute on Aging, the Alzheimer's Association, and the Johnson and Johnson Foundation.
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