RESUMEN
Tauopathies, such as Alzheimer's disease (AD) and frontotemporal dementia (FTD), are characterized by formation of neurofibrillary tangles consisting of hyperphosphorylated tau. In addition to memory loss, patients experience behavioral symptoms such as agitation, aggression, depression, and insomnia. We explored the behavioral phenotype of a mouse model (rTg4510) carrying the human tau P301L mutation found in a familial form of FTD. We tested these mice in locomotor activity assays as well as in the Morris water maze to access spatial memory. In addition to cognitive impairments, rTg4510 mice exhibited a hyperactivity phenotype which correlated with progression of tau pathology and was dependent on P301L tau transgene expression. The hyperactive phenotype was characterized by significantly increased locomotor activity in a novel and in a simulated home cage environment together with a disturbed day/night cycle. The P301L-tau-dependent hyperactivity and agitative-like phenotype suggests that these mice may form a correlate to some of the behavioral disturbances observed in advanced AD and FTD.
Asunto(s)
Hipercinesia/etiología , Agitación Psicomotora/etiología , Tauopatías/complicaciones , Factores de Edad , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Doxiciclina/uso terapéutico , Conducta Exploratoria/efectos de los fármacos , Humanos , Hipercinesia/prevención & control , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Transgénicos , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Mutación/genética , Agitación Psicomotora/prevención & control , Tauopatías/genética , Tauopatías/patología , Factores de Tiempo , Proteínas tau/genéticaRESUMEN
The formation of neurofibrillary tangles from the assembly of hyperphosphorylated tau leads to dendritic and axonal instability, synaptic degeneration, and neuronal loss. To understand the early physiological consequences of aberrant tau expression, we characterized the physiology of CA1 pyramidal neurons in rTg4510 female mice and non-transgenic (wt) littermate controls. We studied mice at the age of 10-12 weeks where only minimal hyperphosphorylated pretangle tau was present, and 22-24 weeks old mice with significant neurofibrillary tangle pathology. Our electrophysiological analysis included input-output relation, paired-pulse facilitation, and whole cell patch-clamp recordings of neurons to measure action potential threshold and action potential properties, chord-conductance, and characterization of AMPA receptor mediated synaptic transmission. We found that the input-output relation in field (excitatory postsynaptic potentials, EPSP) and whole cell recordings (excitatory postsynaptic currents, EPSC) were impaired in rTg4510 mice compared to wt controls at both ages. We measured a diminished tail current charge after depolarizing voltage input in rTg4510 mice compared to wt in both young and aged mice. Additionally, mini-EPSC properties (peak and decay time) were essentially similar between genotypes and age groups investigated. Surprisingly, in the 22-24 week old group, the mini-EPSC frequency was significantly increased (interevent interval 0.8 ± 0.1 in wt compared to 0.3 ± 0.1 in rTg4510 mice). These data indicate that the developmentally regulated expression of human P301L tau in CA1 pyramidal neurons coincide with changes in neuronal excitability but also that significant presynaptic changes occur late during the progression of tau pathology in this mouse model.
Asunto(s)
Región CA1 Hipocampal/patología , Potenciales Postsinápticos Excitadores/fisiología , Células Piramidales/fisiopatología , Tauopatías/patología , Proteínas tau/metabolismo , Factores de Edad , Animales , Animales Recién Nacidos , Biofisica , Modelos Animales de Enfermedad , Doxiciclina/farmacología , Estimulación Eléctrica , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Humanos , Técnicas In Vitro , Ratones , Ratones Transgénicos , Técnicas de Placa-Clamp , Tauopatías/genética , Proteínas tau/genéticaRESUMEN
Alzheimer's disease (AD) is hypothesized to result from elevated brain levels of beta-amyloid peptide (Abeta) which is the main component of plaques found in AD brains and which cause memory impairment in mice. Therefore, there has been a major focus on the development of inhibitors of the Abeta producing enzymes gamma-secretase and beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). In this study, we investigated the Abeta-lowering effects of the BACE1 inhibitor LY2434074 in vitro and in vivo, comparing it to the well characterized gamma-secretase inhibitor LY450139. We sampled interstitial fluid Abeta from awake APPswe/PS1dE9 AD mice by in vivo Abeta microdialysis. In addition, we measured levels of endogenous brain Abeta extracted from wildtype C57BL/6 mice. In our in vitro assays both compounds showed similar Abeta-lowering effects. However, while systemic administration of LY450139 resulted in transient reduction of Abeta in both in vivo models, we were unable to show any Abeta-lowering effect by systemic administration of the BACE1 inhibitor LY2434074 despite brain exposure exceeding the in vitro IC(50) value several fold. In contrast, significant reduction of 40-50% of interstitial fluid Abeta and wildtype cortical Abeta was observed when infusing LY2434074 directly into the brain by means of reverse microdialysis or by dosing the BACE1 inhibitor to p-glycoprotein (p-gp) mutant mice. The effects seen in p-gp mutant mice and subsequent data from our cell-based p-gp transport assay suggested that LY2434074 is a p-gp substrate. This may partly explain why BACE1 inhibition by LY2434074 has lower in vivo efficacy, with respect to decreased Abeta40 levels, compared with gamma-secretase inhibition by LY450139.