RESUMEN
RATIONALE: Diabetes mellitus (DM) is a major risk factor for Alzheimer's disease and vascular dementia. Few animal models exist that focus on the metabolic contributions to dementia onset and progression. Thus, there is strong scientific rationale to explore the effects of streptozotocin (STZ), a diabetogenic compound, on vascular and inflammatory changes within the brain. OBJECTIVE AND METHODS: The present study was designed to evaluate the effect of staggered, low-dose administration of STZ on behavioral and cognitive deficits, neuroinflammation, tau pathology, and histopathological alterations related to dementia. RESULTS: Staggered administration (Days 1, 2, 3, 14, 15) of streptozotocin (40â¯mg/kg/mL) induced a diabetic-like state in mice, resulting in sustained hyperglycemia. STZ-treated animals displayed memory deficits in the novel object recognition task as well as increased tau phosphorylation and increased neuroinflammation. Additionally, STZ led to altered insulin signaling, exhibited by decreased plasma insulin and decreased levels of insulin degrading enzyme and pAKT within the hippocampus. CONCLUSIONS: STZ-treated animals exhibit cognitive deficits and histopathological changes seen in dementia. This model of dementia warrants continued investigation to better understand the role that DM plays in dementia-related alterations.
Asunto(s)
Enfermedad de Alzheimer/etiología , Demencia Vascular/etiología , Diabetes Mellitus Experimental/complicaciones , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/psicología , Animales , Encéfalo/irrigación sanguínea , Encéfalo/inmunología , Encéfalo/patología , Demencia Vascular/metabolismo , Demencia Vascular/patología , Demencia Vascular/psicología , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/psicología , Hemorragia/patología , Hiperglucemia/metabolismo , Hiperglucemia/patología , Hiperglucemia/psicología , Inflamación/etiología , Inflamación/metabolismo , Inflamación/patología , Inflamación/psicología , Insulina/metabolismo , Discapacidades para el Aprendizaje/metabolismo , Discapacidades para el Aprendizaje/patología , Masculino , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/patología , Ratones Endogámicos C57BL , Microvasos/patología , Estreptozocina/administración & dosificación , Proteínas tau/metabolismoRESUMEN
Lipopolysaccharide (LPS) is often used to investigate the exacerbatory effects of an immune-related challenge in transgenic models of various neurodegenerative diseases. However, the effects of this inflammatory challenge in an insulin resistant brain state, as seen in diabetes mellitus, a major risk factor for both vascular dementia (VaD) and Alzheimer's disease (AD), is not as well characterized. We investigated the effects of an LPS-induced inflammatory challenge on behavioral and biological parameters following intracerebroventricular (ICV) injection of streptozotocin (STZ) in male Sprague-Dawley rats. Subjects received a one-time bilateral ICV infusion of STZ (25 mg/mL, 8 µL per ventricle) or ACSF. One week following ICV infusions, LPS (1 mg/mL, i.p.) or saline was administered to activate the immune system. Behavioral testing began on the 22nd day following STZ-ICV infusion, utilizing the open field and Morris water maze (MWM) tasks. Proteins related to immune function, learning and memory, synaptic plasticity, and key histopathological markers observed in VaD and AD were evaluated. The addition of an LPS-induced immune challenge partially attenuated spatial learning and memory deficits in the MWM in STZ-ICV injected animals. Additionally, LPS administration to STZ-treated animals partially mitigated alterations observed in several protein levels in STZ-ICV alone, including NR2A, GABA(B1), and ß-amyloid oligomers. These results suggest that an acute LPS-inflammatory response has a modest protective effect against some of the spatial learning and memory deficits and protein alterations associated with STZ-ICV induction of an insulin resistant brain state.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Inflamación/inducido químicamente , Lipopolisacáridos/toxicidad , Estreptozocina/administración & dosificación , Péptidos beta-Amiloides/metabolismo , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Factores de Intercambio de Guanina Nucleótido/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inflamación/metabolismo , Inflamación/fisiopatología , Inyecciones Intraventriculares , Interleucina-6/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Factores de TiempoRESUMEN
The underlying mechanisms of schizophrenia pathogenesis are not well understood. Increasing evidence supports the glutamatergic hypothesis that posits a hypofunction of the N-methyl D-aspartate (NMDA) receptor on specific gamma amino-butyric acid (GABA)-ergic neurons may be responsible for the disorder. Alterations in the GABAergic system have been observed in schizophrenia, most notably a change in the expression of parvalbumin (PV) in the cortex and hippocampus. Several reports also suggest abnormal neuronal migration may play a role in the etiology of schizophrenia. The current study examined the positioning and distribution of PV-positive cells in the hippocampus following chronic treatment with the NMDA receptor antagonist ketamine. A robust increase was found in the number of PV-positive interneurons located outside the stratum oriens (SO), the layer where most of these cells are normally localized, as well as an overall numerical increase in CA3 PV cells. These results suggest ketamine leads to an abnormal distribution of PV-positive cells, which may be indicative of aberrant migratory activity and possibly related to the Morris water maze deficits observed. These findings may also be relevant to alterations observed in schizophrenia populations.