Alzheimer’s disease is proving to be one of the major obstacles to the lengthening of the lifespan of human beings. The rising costs of healthcare are stunning and the individual costs cannot be fathomed. The contributions from other types of CNS cells, such as inflammatory microglia and reactive astrocytes, cannot be ignored. However, a current research carried out by researchers in the UCSD Neuroscience Department has confirmed an observation that has been ongoing for 20 years at the molecular level. The research shows that abnormal neuronal trafficking is linked with the development and progression of Alzheimer’s disease.
Cellular trafficking is the transport of materials from outside of a cell or the movement of synthesized proteins within the boundaries of a cell. Figuratively, these processes are quite intricate with intricate steps, rhythms, tempos and changing partners, just like in a complex folk dance. In diseases such as Alzehimer’s disorder, these crucial steps may be missing, blocked, or there may be a change of direction of the music. In 1997, researcher Cataldo et al envisioned one of these dancing steps in the pyramidal neurons with the use of a microscope. His group discovered that the endosomal compartment, which is an initial vesicle in the cellular movement, is enlarged in the neurons of AD patients compared to the non-disease controls.
At this time, researchers globally were just starting to understand the endocytotic machinery and very little was known regarding its signaling properties and functions. Today, scientists have a better understanding of the processes. We can now understand simulation of the membrane receptors, initial intracellular signaling cascades, the functions of the endosomes as indicator/signaling platforms, sorting compartments and recycling sections.
The lysosome/endosome pathway is interrupted in the initial course of both Down syndrome and Alzheimer’s disease. Most of the major trafficking steps associated with Alzeimer’s disorder have recently discovered mutations. In other words, there are changes in the protein expression. However, scientists are yet to understand how dysfunction in this pathway affects the development of these diseases.
The ApoE4 was discovered in the early 1990’s. This is the first key variant that is directly linked with the development of Alzeimer’s disorder. The uptake of the ApoE in the central nervous system is through the clarithin-mediated endocytosis by the LRP1. There is a decreased expression of the ApoE in patients suffering from AD.
The clarithin coat is important for the fusion with the endosomes. PICALM, with identified extremely penetrant mutations associated with AD, recruits the clathrin to the cell membrane. ApoE will then transport this to the initial endosomes and can utilize several subsequent itineraries through the late endosomes, then the golgi sacks or the lysosomes for breakdown.
The new study now concentrates on the early endosomes that are marked by the small Rab5 molecular switch. When the Rab5 is continuously “on”, the endosomes will become enlarged because cargo is not precisely handed off in a timely fashion.UCSD researchers have discovered that in AD patients, the Rab5 is dysfunctionally activated. This results in early signaling and abnormal trafficking. Since the movement of cargo in the early transition is hindered or blocked, the neurons lack nuclear translocation, which is vital for transcriptional regulation, degradation or recycling of membrane receptors and transport of cellular nutrients.