RESUMO
Neurodegeneration correlates with Alzheimer's disease (AD) symptoms, but the molecular identities of pathogenic amyloid ß-protein (Aß) oligomers and their targets, leading to neurodegeneration, remain unclear. Amylospheroids (ASPD) are AD patient-derived 10- to 15-nm spherical Aß oligomers that cause selective degeneration of mature neurons. Here, we show that the ASPD target is neuron-specific Na(+)/K(+)-ATPase α3 subunit (NAKα3). ASPD-binding to NAKα3 impaired NAKα3-specific activity, activated N-type voltage-gated calcium channels, and caused mitochondrial calcium dyshomeostasis, tau abnormalities, and neurodegeneration. NMR and molecular modeling studies suggested that spherical ASPD contain N-terminal-Aß-derived "thorns" responsible for target binding, which are distinct from low molecular-weight oligomers and dodecamers. The fourth extracellular loop (Ex4) region of NAKα3 encompassing Asn(879) and Trp(880) is essential for ASPD-NAKα3 interaction, because tetrapeptides mimicking this Ex4 region bound to the ASPD surface and blocked ASPD neurotoxicity. Our findings open up new possibilities for knowledge-based design of peptidomimetics that inhibit neurodegeneration in AD by blocking aberrant ASPD-NAKα3 interaction.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/toxicidade , ATPase Trocadora de Sódio-Potássio/metabolismo , Doença de Alzheimer/patologia , Sequência de Aminoácidos , Animais , Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Células Cultivadas , Células HEK293 , Homeostase/efeitos dos fármacos , Humanos , Espectrometria de Massas , Modelos Biológicos , Modelos Moleculares , Imagem Molecular , Dados de Sequência Molecular , Peso Molecular , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Peptídeos/metabolismo , Agregados Proteicos , Ligação Proteica/efeitos dos fármacos , Ratos , Transdução de Sinais/efeitos dos fármacos , Sódio/metabolismo , ATPase Trocadora de Sódio-Potássio/químicaRESUMO
The suggested role of cellular prion protein (PrP (C) ) in mediating the toxic effects of oligomeric amyloid ß peptide (Aß) in Alzheimer disease (AD) is controversial. To address the hypothesis that variable PrP (C) expression is involved in AD pathogenesis, we analyzed PrPC expression in the frontal and temporal cortices and hippocampus of individuals with no cognitive impairment (NCI), amnestic mild cognitive impairment (aMCI), mild AD (mAD), and AD. We found that PrP (C) expression in all brain regions was not significantly altered among the various patient groups. In addition, PrP (C) levels in all groups did not correlate with expression of methionine (M) or valine (V) at codon 129 of the PrP gene, a polymorphism that has been linked in some studies to increased risk for AD, and which occurs in close proximity to the proposed binding region for the oligomeric Aß peptide. Our results indicate that, if PrP (C) is involved in mediating the toxic effects of the oligomeric Aß peptide, these effects occur independently of steady state levels of PrP or the codon 129 polymorphism.