RESUMEN
Alzheimer's disease (AD) pathology precedes the onset of clinical symptoms by several decades. Thus, biomarkers are required to identify prodromal disease stages to allow for the early and effective treatment. The methoxy-X04-derivative BSC4090 is a fluorescent ligand which was designed to target neurofibrillary tangles in AD. BSC4090 staining was previously detected in post-mortem brains and olfactory mucosa derived from AD patients. We tested BSC4090 as a potential diagnostic marker of prodromal and early AD using olfactory mucosa biopsies from 12 individuals with AD, 13 with mild cognitive impairment (MCI), and 10 cognitively normal (CN) controls. Receiver-operating curve analysis revealed areas under the curve of 0.78 for AD versus CN and of 0.86 for MCI due to AD versus MCI of other causes. BSC4090 labeling correlated significantly with cerebrospinal fluid levels of tau protein phosphorylated at T181. Using NMR spectroscopy, we find that BSC4090 binds to fibrillar and pre-fibrillar but not to monomeric tau. Thus, BSC4090 may be an interesting candidate to detect AD at the early disease stages.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico , Compuestos de Bencilideno , Disfunción Cognitiva/diagnóstico , Colorantes Fluorescentes , Mucosa Olfatoria/metabolismo , Pirimidinas , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/patología , Compuestos de Bencilideno/química , Biopsia , Estudios de Casos y Controles , Femenino , Colorantes Fluorescentes/química , Humanos , Espectroscopía de Resonancia Magnética , Masculino , Pruebas de Estado Mental y Demencia , Microscopía Confocal , Microscopía Electrónica de Transmisión , Persona de Mediana Edad , Mucosa Olfatoria/patología , Mucosa Olfatoria/ultraestructura , Síntomas Prodrómicos , Pirimidinas/química , EstilbenosRESUMEN
Alzheimer's disease is a devastating neurodegenerative disease eventually leading to dementia. An effective treatment does not yet exist. Here we show that oral application of the compound anle138b restores hippocampal synaptic and transcriptional plasticity as well as spatial memory in a mouse model for Alzheimer's disease, when given orally before or after the onset of pathology. At the mechanistic level, we provide evidence that anle138b blocks the activity of conducting Aß pores without changing the membrane embedded Aß-oligomer structure. In conclusion, our data suggest that anle138b is a novel and promising compound to treat AD-related pathology that should be investigated further.