Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP.
Cell Death Dis
; 3: e326, 2012 Jun 21.
Article
em En
| MEDLINE
| ID: mdl-22717581
ABSTRACT
Neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD). The main component of NFTs is TAU, a highly soluble microtubule-associated protein. However, when TAU is cleaved at Asp421 by caspases it becomes prone to aggregation leading to NFTs. What triggers caspase activation resulting in TAU cleavage remains unclear. We investigated in rat cortical neurons a potential coordination between proteasome impairment and caspase activation. We demonstrate that upon proteasome inhibition, the early accumulation of detergent-soluble ubiquitinated (SUb) proteins paves the way to caspase activation and TAU pathology. This occurs with two drugs that inhibit the proteasome by different means the product of inflammation prostaglandin J2 (PGJ2) and epoxomicin. Our results pinpoint a critical early event, that is, the buildup of SUb proteins that contributes to caspase activation, TAU cleavage, TAU/Ub-protein aggregation and neuronal death. Furthermore, to our knowledge, we are the first to demonstrate that elevating cAMP in neurons with dibutyryl-cAMP (db-cAMP) or the lipophilic peptide PACAP27 prevents/diminishes caspase activation, TAU cleavage and neuronal death induced by PGJ2, as long as these PGJ2-induced changes are moderate. db-cAMP also stimulated proteasomes, and mitigated proteasome inhibition induced by PGJ2. We propose that targeting cAMP/PKA to boost proteasome activity in a sustainable manner could offer an effective approach to avoid early accumulation of SUb proteins and later caspase activation, and TAU cleavage, possibly preventing/delaying AD neurodegeneration.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas tau
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CMP Cíclico
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Complexo de Endopeptidases do Proteassoma
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Neurônios
Limite:
Animals
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2012
Tipo de documento:
Article
País de afiliação:
Estados Unidos