RESUMEN
Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer's disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery of the active spliced transcription factor X-Box binding protein 1s (XBP1s) in the hippocampus rescued spine density, synaptic plasticity and memory function in a mouse model of AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), a protein that controls synaptic plasticity. In addition, we found reduced levels of Kal7 in primary neurons exposed to Aß oligomers, transgenic mouse models and human AD brains. Short hairpin RNA-mediated knockdown of Kal7 altered synaptic plasticity and memory formation in naive mice. Further, reduction of endogenous Kal7 compromised the beneficial effects of XBP1s in Alzheimer's model. Hence, our findings reveal that XBP1s is neuroprotective through a mechanism that engages Kal7 pathway with therapeutic implications in AD pathology.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína 1 de Unión a la X-Box/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/genética , Animales , Células CHO , Cricetulus , Modelos Animales de Enfermedad , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Hipocampo/metabolismo , Humanos , Masculino , Ratones , Ratones Noqueados , Persona de Mediana Edad , Plasticidad Neuronal , Neuronas/metabolismo , Cultivo Primario de Células , Factores de Transcripción/metabolismo , Proteína 1 de Unión a la X-Box/genética , Adulto JovenRESUMEN
Amyloid precursor protein (APP) has been the subject of intense research to uncover its implication in Alzheimer's disease. Its physiological function is, however, still poorly understood. Herein, we investigated its possible influence on the development of cultured hippocampal neurons. A peptide corresponding to the APP intracellular domain linked to a cell-penetrating peptide was used to alter the interactions of APP with its cytosolic partners. This treatment promoted the concentration of the cytosolic GTPase dynamin 3 (Dyn3) in neurite segments when most untreated cells displayed a homogenous punctate distribution of Dyn3. The Dyn3-labelled segments were excluded from those revealed by APP staining after aldehyde fixation. Interestingly, after aldehyde fixation MAP2 also labelled segments excluded from APP-stained segments. Thus APP is also a marker for the spacing pattern of neurites demonstrated by Taylor & Fallon (2006)J. Neurosci., 26, 1154-4463.