Alzheimer’s Disease: Do We Need A Traffic Cop To Prevent Pathology?

Alzheimer’s disease (AD) is turning out to be one of the greatest challenges to lengthening our lifespan. The costs to our healthcare industry are staggering and the personal costs have no price tag. Although the contributions from other CNS cell types, like reactive astrocytes and inflammatory microglia, are not to be discounted; recently published work by scientists in the UCSD Neuroscience Department confirm a 20-year old observation at a molecular level, that dysfunctional neuronal trafficking is associated with the development of AD.

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The movement of materials from outside a cell or transport of synthesized proteins within a cell is generally termed “cellular trafficking”. Metaphorically, these processes represent a complex folk dance, with rapidly changing partners, rhythm and tempo changes and intricate steps. In diseases like AD, these steps can be blocked, missing “dance partners” or have the music change direction. Cataldo et al., used microscopy to visualize one of these dance steps in pyramidal neurons in 1997 1. His group found that an early vesicle in cellular trafficking, the endosomal compartment, is enlarged in AD neurons compared to non-disease controls. At the time, endocytotic machinery was just being elucidated and little was known about the functions and signaling properties of these compartments. In subsequent years, we have gained a greater understanding of the processes from stimulation of membrane receptors, to early intracellular signaling cascades, to the function of endosomes as signaling platforms, recycling compartments and sorting compartments.

Many of these key trafficking steps have AD associated protein expression changes or newly recognized mutations. Early in the 1990’s, the first major variant clearly associated with the development of AD was identified: ApoE4. In the CNS, ApoE uptake is through clathrin – mediated endocytosis by LRP1, which has decreased expression in AD patients. The clathrin coat is critical for later fusion with endosomes. PICALM, with known highly penetrant AD associated mutations, recruits clathrin to the membrane. ApoE further traffics to early endosomes and can take one of several subsequent routes through late endosomes to golgi stacks or directly to lysosomes for degradation. The current study focuses in on early endosomes, marked by the small molecular switch Rab5. When Rab5 is constitutively “on”, endosomes become enlarged since cargo isn’t handed off in a precisely timed fashion. The researchers at UCSD have found that Rab5 is abnormally activated in AD, causing early signaling and trafficking dysfunction, just one more piece in the trafficking puzzle 2. With cargo movement being blocked or hindered in this early transition, neurons are deprived of nuclear translocation for transcriptional regulation, cargo transport of cellular nutrients and required recycling or degradation of membrane receptors.

1. Cataldo AM, Barnett JL, Pieroni C, & Nixon RA (1997) Increased neuronal endocytosis and protease delivery to early endosomes in sporadic Alzheimer’s disease: neuropathologic evidence for a mechanism of increased beta-amyloidogenesis. J Neurosci 17(16):6142-6151.
2. Xu W, et al. (2016) Amyloid precursor protein-mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration. J Clin Invest.

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