Proteins Recruited to Exosomes by Tau Overexpression Implicate Novel Cellular Mechanisms Linking Tau Secretion with Alzheimer's Disease

Abstract

Tau misprocessing to form aggregates and other toxic species has emerged as a major feature in our developing understanding of the etiology and pathogenesis of Alzheimer's Disease (AD). The significance of tau misprocessing in AD has been further emphasized by recent studies showing that tau can be secreted from neurons via exosomes and may itself be an important agent in the spreading of neurofibrillary lesions within the brain. Tau secretion occurs most readily under disease-associated conditions in cellular models, suggesting that cellular changes responsible for secretion, possibly including tau oligomerization, could play a key role in the propagation of neurofibrillary lesions in neurodegenerative disease. Here we show that overexpression of 4R0N human tau in neuroblastoma cells recruits mitochondrial and axonogenesis-associated proteins relevant to neurodegeneration into the exosomal secretion pathway via distinct mechanisms. The recruitment of mitochondrial proteins appears to be linked to autophagy disruption (exophagy) in multiple neurodegenerative conditions but but has few known direct links to AD and tau. By contrast, the involvement of synaptic plasticity and axonogenesis markers is highly specific to both tau and AD and may be relevant to the reactivation of developmental programs involving tau in AD and the recently demonstrated ability of secreted tau to establish tissue distribution gradients in CNS neuropil. We also found a highly significant correlation between genes that are significantly downregulated in multiple forms of AD and proteins that have been recruited to exosomes by tau, which we interpret as strong evidence for the central involvement of tau secretion in AD cytopathogenesis. Our results suggest that multiple cellular mechanisms may link tau secretion to both toxicity and and neurofibrillary lesion spreading in Alzheimer's disease and other tauopathies.

Alzheimer’s disease and chronic traumatic encephalopathy: Distinct but possibly overlapping disease entities

“…89 Cells that survive the primary insult are subject to tau-mediated mitochondrial damage, which occurs over an extended period of time. 90 Tau can increase glutathione leading to increased permeability of mitochondrial membranes. In AD, damaged mitochondria can no longer generate ATP leaving neuronal cells susceptible to metabolic crisis.…”

Insulin resistance in Alzheimer's disease

“…Moreover, astrocytic derived EV’s have been shown to mediate apoptosis leading to brain cell loss [201]. Lastly, there is evidence to support that tau overexpression selectively recruits mitochondrial proteins implicated in neurodegeneration to exosomes, providing a novel link between tau exosome secretion and AD pathology [202]. However, there are also findings that support a neuroprotective role of exosomes in the face of neurodegenerative diseases.…”

Extracellular vesicles and intercellular communication within the nervous system

“…At present there is some controversy in the field as to the role of EVs in AD; while some studies (59)(60)(61) suggest that exosome-associated Aβ is protective, other studies suggest that exosome-associated Aβ contributes neurotoxic amyloid formation (56,(62)(63)(64)(65). Moreover, misfolded tau protein, which is implicated in Aβ aggregate formation, may also be released from neurons via EVs (66). EV release of misfolded tau appears to recruit other proteins into EVs, including mitochondrial-, synaptic-, and axonogenesis-related proteins that have been linked to the pathogenesis of AD and other neurodegenerative diseases (i.e., tauopathies) (66).…”

“…Moreover, misfolded tau protein, which is implicated in Aβ aggregate formation, may also be released from neurons via EVs (66). EV release of misfolded tau appears to recruit other proteins into EVs, including mitochondrial-, synaptic-, and axonogenesis-related proteins that have been linked to the pathogenesis of AD and other neurodegenerative diseases (i.e., tauopathies) (66). In PD, the accumulation of misfolded α-synuclein has been associated with EV release by neurons (67,68); however, in PD as well as other neurodegenerative processes, the potential pathways of cell-to-cell spreading and disease propagation are still being evaluated (68,69).…”