Proteins recruited to exosomes by tau overexpression implicate novel cellular mechanisms linking tau secretion with Alzheimer's disease.
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 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 neurofibrillary lesion spreading in AD and other tauopathies.
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA Mass Bay Community College, Science Department, STEM Division, MA, USA.
Sudad
S
Saman
Boston University Chemical Instrumentation Center, Department of Chemistry, Boston, MA, USA.
Norman C Y
NC
Lee
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Itoro
I
Inoyo
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Jun
J
Jin
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Zhihan
Z
Li
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA Mass Bay Community College, Science Department, STEM Division, MA, USA.
Thomas
T
Doyle
GRECC Unit, Veterans Administration Medical Center, Bedford, MA, USA and Departments of Neurology and Pathology, Boston University School of Medicine, Boston, MA, USA.
Ann C
AC
McKee
Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
Garth F
GF
Hall
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D055354:Exosomes; D006801:Humans; D007798:Lampreys; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins
Alzheimer's disease; autophagy; endosome; exosome; gene downregulation; mitochondria; morphogen; tau; tau lesion spreading; tau secretion