AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons

G. Amadoro, V. Corsetti, F. Florenzano, A. Atlante, M. T. Ciotti, M. P. Mongiardi, R. Bussani, V. Nicolin, S. L. Nori, M. Campanella, P. Calissano

Research output: Contribution to journalArticle

Abstract

Functional as well as structural alterations in mitochondria size, shape and distribution are precipitating, early events in progression of Alzheimer's Disease (AD). We reported that a 20-22kDa NH2-tau fragment (aka NH2htau), mapping between 26 and 230 amino acids of the longest human tau isoform, is detected in cellular and animal AD models and is neurotoxic in hippocampal neurons. The NH2htau -but not the physiological full-length protein- interacts with Aβ at human AD synapses and cooperates with it in inhibiting the mitochondrial ANT-1-dependent ADP/ATP exchange. Here we show that the NH2htau also adversely affects the interplay between the mitochondria dynamics and their selective autophagic clearance. Fragmentation and perinuclear mislocalization of mitochondria with smaller size and density are early found in dying NH2htau-expressing neurons. The specific effect of NH2htau on quality control of mitochondria is accompanied by (i) net reduction in their mass in correlation with a general Parkin-mediated remodeling of membrane proteome; (ii) their extensive association with LC3 and LAMP1 autophagic markers; (iii) bioenergetic deficits and (iv) in vitro synaptic pathology. These results suggest that NH2htau can compromise the mitochondrial biology thereby contributing to AD synaptic deficits not only by ANT-1 inactivation but also, indirectly, by impairing the quality control mechanism of these organelles.

Original languageEnglish
Pages (from-to)489-507
Number of pages19
JournalNeurobiology of Disease
Volume62
DOIs
Publication statusPublished - 2014

Keywords

  • Alzheimer's Disease (AD)
  • Autophagy
  • Mitochondrial dynamics
  • Neurodegeneration
  • Synapse(s)

ASJC Scopus subject areas

  • Neurology

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    Amadoro, G., Corsetti, V., Florenzano, F., Atlante, A., Ciotti, M. T., Mongiardi, M. P., Bussani, R., Nicolin, V., Nori, S. L., Campanella, M., & Calissano, P. (2014). AD-linked, toxic NH2 human tau affects the quality control of mitochondria in neurons. Neurobiology of Disease, 62, 489-507. https://doi.org/10.1016/j.nbd.2013.10.018