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

45 Citations (Scopus)

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

Fingerprint

Synapses
Alzheimer Disease
Mitochondria
Tauopathies
Neurofibrillary Tangles
tau Proteins
Synaptosomes
Neocortex
Amyloid Plaques
Brain
Drug Discovery
Amyloid
Neurodegenerative Diseases
Organelles
Hippocampus
Pathology
Neurons
Peptides
Enzymes

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)

Cite this

A NH2 tau fragment targets neuronal mitochondria at AD synapses : Possible implications for neurodegeneration. / Amadoro, Giuseppina; Corsetti, Veronica; Stringaro, Annarita; Colone, Marisa; D'Aguanno, Simona; Meli, Giovanni; Ciotti, Mariateresa; Sancesario, Giuseppe; Cattaneo, Antonino; Bussani, Rossana; Mercanti, Delio; Calissano, Pietro.

In: Journal of Alzheimer's Disease, Vol. 21, No. 2, 2010, p. 445-470.

Research output: Contribution to journalArticle

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, vol. 21, no. 2, pp. 445-470. https://doi.org/10.3233/JAD-2010-100120
Amadoro, Giuseppina ; Corsetti, Veronica ; Stringaro, Annarita ; Colone, Marisa ; D'Aguanno, Simona ; Meli, Giovanni ; Ciotti, Mariateresa ; Sancesario, Giuseppe ; Cattaneo, Antonino ; Bussani, Rossana ; Mercanti, Delio ; Calissano, Pietro. / A NH2 tau fragment targets neuronal mitochondria at AD synapses : Possible implications for neurodegeneration. In: Journal of Alzheimer's Disease. 2010 ; Vol. 21, No. 2. pp. 445-470.
@article{483b0d9e64724910a98c0849129cde8b,
title = "A NH2 tau fragment targets neuronal mitochondria at AD synapses: Possible implications for neurodegeneration",
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.",
keywords = "Alzheimer's disease, amyloid, mitochondria, neurodegeneration, synapse(s), tau",
author = "Giuseppina Amadoro and Veronica Corsetti and Annarita Stringaro and Marisa Colone and Simona D'Aguanno and Giovanni Meli and Mariateresa Ciotti and Giuseppe Sancesario and Antonino Cattaneo and Rossana Bussani and Delio Mercanti and Pietro Calissano",
year = "2010",
doi = "10.3233/JAD-2010-100120",
language = "English",
volume = "21",
pages = "445--470",
journal = "Journal of Alzheimer's Disease",
issn = "1387-2877",
publisher = "IOS Press",
number = "2",

}

TY - JOUR

T1 - A NH2 tau fragment targets neuronal mitochondria at AD synapses

T2 - Possible implications for neurodegeneration

AU - Amadoro, Giuseppina

AU - Corsetti, Veronica

AU - Stringaro, Annarita

AU - Colone, Marisa

AU - D'Aguanno, Simona

AU - Meli, Giovanni

AU - Ciotti, Mariateresa

AU - Sancesario, Giuseppe

AU - Cattaneo, Antonino

AU - Bussani, Rossana

AU - Mercanti, Delio

AU - Calissano, Pietro

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - amyloid

KW - mitochondria

KW - neurodegeneration

KW - synapse(s)

KW - tau

UR - http://www.scopus.com/inward/record.url?scp=77957563700&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77957563700&partnerID=8YFLogxK

U2 - 10.3233/JAD-2010-100120

DO - 10.3233/JAD-2010-100120

M3 - Article

C2 - 20571215

AN - SCOPUS:77957563700

VL - 21

SP - 445

EP - 470

JO - Journal of Alzheimer's Disease

JF - Journal of Alzheimer's Disease

SN - 1387-2877

IS - 2

ER -