A NH2 tau fragment targets neuronal mitochondria at AD synapses: Possible implications for neurodegeneration

Giuseppina Amadoro, Veronica Corsetti, Annarita Stringaro, Marisa Colone, Simona D'Aguanno, Giovanni Meli, Mariateresa Ciotti, Giuseppe Sancesario, Antonino Cattaneo, Rossana Bussani, Delio Mercanti, Pietro Calissano

Research output: Contribution to journalArticle

Abstract

Synapses are ultrastructural sites for memory storage in brain, and synaptic damage is the best pathologic correlate of cognitive decline in Alzheimer's disease (AD). Post-translational hyperphosphorylation, enzyme-mediated truncation, conformational modifications, and aggregation of tau protein into neurofibrillary tangles (NFTs) are hallmarks for a heterogeneous group of neurodegenerative disorders, so-called tauopathies. AD is a secondary tauopathy since it is pathologically distinguished by the presence of amyloid-β (Aβ)-containing senile plaques and the presence of tau-positive NFTs in the neocortex and hippocampus. Here, we report that a 20-22 kDa NH2-truncated tau fragment is largely enriched in human mitochondria from cryopreserved synaptosomes of AD brains and that its amount in terminal fields correlates with the pathological synaptic changes and with the organelle functional impairment. This NH2-truncated tau form is also found in other human, not AD-tauopathies, while its presence in AD patients is linked to Aβ multimeric species and likely to pathology severity. Finally native, patient-derived, Aβ oligomers-enriched extracts likely impair the mitochondrial funct on by the in vitro production of 20-22 kDa NH2-tau fragments in mature human SY5Y and in rat hippocampal neurons. Thus our findings suggest that the mitochondrial NH2-derived tau peptide distribution may exacerbate the synapse degeneration occurring in tauopathies, including AD, and sustain the in vivo NH-2 tau cleavage inhibitors as an alternative drug discovery strategies for AD therapy.

Original languageEnglish
Pages (from-to)445-470
Number of pages26
JournalJournal of Alzheimer's Disease
Volume21
Issue number2
DOIs
Publication statusPublished - 2010

Keywords

  • Alzheimer's disease
  • amyloid
  • mitochondria
  • neurodegeneration
  • synapse(s)
  • tau

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Geriatrics and Gerontology
  • Clinical Psychology
  • Medicine(all)

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  • Cite this

    Amadoro, G., Corsetti, V., Stringaro, A., Colone, M., D'Aguanno, S., Meli, G., Ciotti, M., Sancesario, G., Cattaneo, A., Bussani, R., Mercanti, D., & Calissano, P. (2010). A NH2 tau fragment targets neuronal mitochondria at AD synapses: Possible implications for neurodegeneration. Journal of Alzheimer's Disease, 21(2), 445-470. https://doi.org/10.3233/JAD-2010-100120