RESUMO
γ-secretase inhibitors (GSIs) have been developed to reduce amyloid-ß (Aß) production for the treatment of Alzheimer's disease by inhibiting the cleavage of amyloid precursor protein (APP). However, cross-inhibitory activity on the processing of Notch can cause adverse reactions. To avoid these undesirable effects, γ-secretase modulators (GSMs) are being developed to selectively reduce toxic Aß production without perturbing Notch signaling. As it is also known that GSIs can cause a paradoxical increase of plasma Aß over the baseline after a transient reduction (known as Aß-rebound), we asked if GSMs would cause a similar rebound and what the potential mechanism might be. Our studies were performed with one GSI (LY-450139) and two chemically distinct GSMs. Although LY-450139 caused Aß-rebound as expected in rat plasma, the two GSMs did not. Inhibition of APP processing by LY-450139 induced an accumulation of γ-secretase substrates, α- and ß-C-terminal fragments of APP, but neither GSM caused such an accumulation. In conclusion, we discover that GSMs, unlike GSIs, do not cause Aß-rebound, possibly because of the lack of accumulation of ß-C-terminal fragments. GSMs may be superior to GSIs in the treatment of Alzheimer's disease not only by sparing Notch signaling but also by avoiding Aß-rebound.
Assuntos
Alanina/análogos & derivados , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Secretases da Proteína Precursora do Amiloide/efeitos dos fármacos , Peptídeos beta-Amiloides/biossíntese , Azepinas/farmacologia , Alanina/farmacocinética , Alanina/farmacologia , Peptídeos beta-Amiloides/genética , Animais , Área Sob a Curva , Azepinas/farmacocinética , Linhagem Celular , Células Cultivadas , Cromatografia Líquida de Alta Pressão , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Fragmentos de Peptídeos/metabolismo , Placa Amiloide/patologia , Ratos , Ratos Sprague-Dawley , Receptores Notch/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
The endoplasmic reticulum (ER) is a dynamic multifunction organelle that is responsible for Ca(2+) homeostasis, protein folding, post-translational modification, protein degradation, and transportation of nascent proteins. Disruption of ER architecture might affect the normal physiology of the cell. In yeast, expansion of the ER is observed under unfolded protein response (UPR) and subsequently induces autophagy initiated from the ER. Here, we found that soluble low molecular weight of Abeta disrupted the anchoring between ER and microtubules (MT) and induced collapse of ER. In addition, it decreased the stability of MT. Subsequently, low molecular weight Abeta triggered autophagy and enhanced lysosomal degradation, as shown by electron microscopy and live-cell imaging. Dysfunction of ER can be further proved in postmortem AD brain and transgenic mice bearing APP Swedish mutation by immunohistochemical analysis of calreticulin. Treatment with Taxol, a MT-stabilizing agent, could partially inhibit collapse of the ER and induction of autophagy. The results show that Abeta-induced disruption of MT can affect the architecture of the ER. Collapse/aggregation of the ER may play an important role in Abeta peptide-triggered neurodegenerative processes.
Assuntos
Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Retículo Endoplasmático , Peptídeos beta-Amiloides/genética , Animais , Células Cultivadas , Retículo Endoplasmático/metabolismo , Retículo Endoplasmático/ultraestrutura , Hipocampo/citologia , Humanos , Lisossomos/metabolismo , Lisossomos/ultraestrutura , Camundongos , Camundongos Transgênicos , Microtúbulos/metabolismo , Peso Molecular , Neurônios/citologia , Neurônios/metabolismo , Nocodazol/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/metabolismo , Vacúolos/metabolismoRESUMO
Extracellular amyloid beta (Abeta) that confers neurotoxicity and modulates synaptic plasticity and memory function has been central to the amyloid hypothesis of Alzheimer's disease (AD) pathology. Like many other misfolded proteins identified in neurodegenerative disorders, Abeta also accumulates inside the AD neurons. This intracellular Abeta affects a variety of cellular physiology from protein degradation, axonal transport, autophagy to apoptosis, further documenting the role of Abeta in AD. Therapeutics targeting intracellular Abeta could be effective treatment for AD.