RESUMO
Locus ceruleus (LC) degeneration and loss of cortical noradrenergic innervation occur early in Alzheimer's disease (AD). Although this has been known for several decades, the contribution of LC degeneration to AD pathogenesis remains unclear. We induced LC degeneration with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (dsp4) in amyloid precursor protein 23 (APP23) transgenic mice with a low amyloid load. Then 6 months later the LC projection areas showed a robust elevation of glial inflammation along with augmented amyloid plaque deposits. Moreover, neurodegeneration and neuronal loss significantly increased. Importantly, the paraventricular thalamus, a nonprojection area, remained unaffected. Radial arm maze and social partner recognition tests revealed increased memory deficits while high-resolution magnetic resonance imaging-guided micro-positron emission tomography demonstrated reduced cerebral glucose metabolism, disturbed neuronal integrity, and attenuated acetylcholinesterase activity. Nontransgenic mice with LC degeneration were devoid of these alterations. Our data demonstrate that the degeneration of LC affects morphology, metabolism, and function of amyloid plaque-containing higher brain regions in APP23 mice. We postulate that LC degeneration substantially contributes to AD development.
Assuntos
Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Locus Cerúleo/patologia , Degeneração Neural/patologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/etiologia , Animais , Astrócitos/metabolismo , Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Feminino , Locus Cerúleo/metabolismo , Camundongos , Camundongos Transgênicos , Microglia/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Norepinefrina/metabolismo , Ácido Peroxinitroso/metabolismo , Placa Amiloide/patologia , Tomografia por Emissão de Pósitrons , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
Sepsis is a disease with a high and growing prevalence worldwide. Most studies on sepsis up to date have been focused on reduction of short-term mortality. This study investigates cognitive and neuroanatomical long-term consequences of sepsis in a rat model. Sepsis was induced in male Wistar rats weighing 250-300 g by an i.p. injection of bacterial lipopolysaccharide (LPS, 10 mg/kg). Three months after complete recovery from sepsis, animals showed memory deficits in the radial maze and changes in open field exploratory patterns but unaffected inhibitory avoidance learning. Behavioral findings were matched by sepsis-induced loss of neurons in the hippocampus and the prefrontal cortex on serial sections after NeuN-staining and reduced cholinergic innervation in the parietal cortex measured by immunoradiography of vesicular acetylcholine transporter (VAChT). Together these results suggest that sepsis can induce persistent behavioral and neuroanatomical changes and warrant studies of the neurological long-term consequences of sepsis in humans.