Selective induction of calcineurin activity and signaling by oligomeric amyloid beta

Lindsay C. Reese, Wen Ru Zhang, Kelly Dineley, Rakez Kayed, Giulio Taglialatela

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Aβ) is a signature of AD, evidence suggests that the preplaque small oligomeric Aβ promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Aβ and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Aβ. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Aβ on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Aβ specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Aβ oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Aβ on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Aβ in the aging CNS.

Original languageEnglish (US)
Pages (from-to)824-835
Number of pages12
JournalAging Cell
Volume7
Issue number6
DOIs
StatePublished - 2008

Fingerprint

Calcineurin
Amyloid
Central Nervous System
Carrier Proteins
Alzheimer Disease
bcl-Associated Death Protein
Cell Death
Amyloid beta-Peptides
Memory Disorders
Transgenic Mice
Dementia
Rodentia
Transcription Factors
Phosphorylation

Keywords

  • Alzheimer's disease
  • Amyloidbeta
  • BAD
  • Calcineurin
  • CREB
  • Oligomer

ASJC Scopus subject areas

  • Cell Biology
  • Aging

Cite this

Selective induction of calcineurin activity and signaling by oligomeric amyloid beta. / Reese, Lindsay C.; Zhang, Wen Ru; Dineley, Kelly; Kayed, Rakez; Taglialatela, Giulio.

In: Aging Cell, Vol. 7, No. 6, 2008, p. 824-835.

Research output: Contribution to journalArticle

@article{72d92fa14fac45dc95d7a3d88fbc592d,
title = "Selective induction of calcineurin activity and signaling by oligomeric amyloid beta",
abstract = "Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Aβ) is a signature of AD, evidence suggests that the preplaque small oligomeric Aβ promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Aβ and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Aβ. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Aβ on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Aβ specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Aβ oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Aβ on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Aβ in the aging CNS.",
keywords = "Alzheimer's disease, Amyloidbeta, BAD, Calcineurin, CREB, Oligomer",
author = "Reese, {Lindsay C.} and Zhang, {Wen Ru} and Kelly Dineley and Rakez Kayed and Giulio Taglialatela",
year = "2008",
doi = "10.1111/j.1474-9726.2008.00434.x",
language = "English (US)",
volume = "7",
pages = "824--835",
journal = "Aging Cell",
issn = "1474-9718",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Selective induction of calcineurin activity and signaling by oligomeric amyloid beta

AU - Reese, Lindsay C.

AU - Zhang, Wen Ru

AU - Dineley, Kelly

AU - Kayed, Rakez

AU - Taglialatela, Giulio

PY - 2008

Y1 - 2008

N2 - Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Aβ) is a signature of AD, evidence suggests that the preplaque small oligomeric Aβ promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Aβ and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Aβ. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Aβ on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Aβ specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Aβ oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Aβ on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Aβ in the aging CNS.

AB - Alzheimer's disease (AD) is a terminal age-associated dementia characterized by early synaptic dysfunction and late neurodegeneration. Although the presence of plaques of fibrillar aggregates of the amyloid beta peptide (Aβ) is a signature of AD, evidence suggests that the preplaque small oligomeric Aβ promotes both synaptic dysfunction and neuronal death. We found that young Tg2576 transgenic mice, which accumulate Aβ and develop cognitive impairments prior to plaque deposition, have high central nervous system (CNS) activity of calcineurin (CaN), a phosphatase involved in negative regulation of memory function via inactivation of the transcription factor cAMP responsive element binding proteins (CREB), and display CaN-dependent memory deficits. These results thus suggested the involvement of prefibrillary forms of Aβ. To investigate this issue, we compared the effect of monomeric, oligomeric, and fibrillar Aβ on CaN activity, CaN-dependent pCREB and phosphorylated Bcl-2 Associated death Protein (pBAD) levels, and cell death in SY5Y cells and in rat brain slices, and determined the role of CaN on CREB phosphorylation in the CNS of Tg2576 mice. Our results show that oligomeric Aβ specifically induces CaN activity and promotes CaN-dependent CREB and Bcl-2 Asociated death Protein (BAD) dephosphorylation and cell death. Furthermore, Tg2576 mice display Aβ oligomers and reduced pCREB in the CNS, which is normalized by CaN inhibition. These findings suggest a role for CaN in mediating effects of oligomeric Aβ on neural cells. Because elevated CaN levels have been reported in the CNS of cognitively impaired aged rodents, our results further suggest that abnormal CaN hyperactivity may be a common event exacerbating the cognitive and neurodegenerative impact of oligomeric Aβ in the aging CNS.

KW - Alzheimer's disease

KW - Amyloidbeta

KW - BAD

KW - Calcineurin

KW - CREB

KW - Oligomer

UR - http://www.scopus.com/inward/record.url?scp=56849091064&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=56849091064&partnerID=8YFLogxK

U2 - 10.1111/j.1474-9726.2008.00434.x

DO - 10.1111/j.1474-9726.2008.00434.x

M3 - Article

C2 - 18782350

AN - SCOPUS:56849091064

VL - 7

SP - 824

EP - 835

JO - Aging Cell

JF - Aging Cell

SN - 1474-9718

IS - 6

ER -