RESUMEN
OBJECTIVE: LR11 (aka sorLA) is a multifunctional neuronal receptor that binds apolipoprotein E and interacts with amyloid precursor protein to regulate amyloidogenesis. Reduced expression of LR11, as occurs in the brains of individuals with Alzheimer's disease (AD), increases amyloidogenesis, and variants in the gene that encodes LR11, SORL1, have recently been linked to risk for late-onset AD. In this study, we sought to determine whether reduced expression of LR11 occurs early in the disease process and whether protein levels in cortical neurons are associated with clinical and pathological changes in mild cognitive impairment (MCI), a condition that may represent prodromal AD. METHODS: A novel quantitative immunohistochemical approach was used to measure LR11 levels in brain tissue collected from subjects diagnosed antemortem with either no cognitive impairment, MCI, or AD from the Rush University Religious Orders Study. RESULTS: LR11 levels in MCI were intermediate between no cognitive impairment and AD. LR11 expression was heterogeneous in MCI, forming low- and high-level LR11 subgroups. MCI subjects with low LR11 were significantly more cognitively impaired than the high LR11 subjects. We also found a significant correlation between cognitive performance and LR11 levels across all clinical groups examined. There was no association between LR11 and plaque and tangle pathology. INTERPRETATION: Neuronal LR11 levels are reduced in prodomal AD. The correlation between LR11 expression and cognitive performance indicates that reduced LR11 levels reflect disease severity and may predict progression to AD in a subgroup of individuals with MCI.
Asunto(s)
Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/psicología , Proteínas Relacionadas con Receptor de LDL/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Neuronas/metabolismo , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/patología , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Placa Amiloide/patología , Índice de Severidad de la Enfermedad , Coloración y Etiquetado , Tauopatías/patologíaRESUMEN
We previously demonstrated that treating gravid female rats with the bacteriotoxin lipopolysaccharide (LPS) led to the birth of offspring with fewer than normal dopamine (DA) neurons. This DA neuron loss was long-lived and associated with permanent increases in the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Because of this pro-inflammatory state, we hypothesized that these animals would be more susceptible to subsequent exposure of DA neurotoxins. We tested this hypothesis by treating female Sprague-Dawley rats exposed to LPS or saline prenatally with a subtoxic dose of the DA neurotoxin rotenone (1.25 mg/kg per day) or vehicle for 14 days when they were 16 months old. After another 14 days, the animals were sacrificed. Tyrosine hydroxylase-immunoreactive (THir) cell counts were used as an index of DA neuron survival. Animals exposed to LPS prenatally or rotenone postnatally exhibited a 22% and 3%, respectively, decrease in THir cell counts relative to controls. The combined effects of prenatal LPS and postnatal rotenone exposure produced a synergistic 39% THir cell loss relative to controls. This loss was associated with decreased striatal DA and increased striatal DA activity ([HVA]/[DA]) and TNFalpha. Animals exposed to LPS prenatally exhibited a marked increase in the number of reactive microglia that was further increased by rotenone exposure. Prenatal LPS exposure also led to increased levels of oxidized proteins and the formation of alpha-Synuclein and eosin positive inclusions resembling Lewy bodies. These results suggest that exposure to low doses of an environmental neurotoxin like rotenone can produce synergistic DA neuron losses in animals with a preexisting pro-inflammatory state. This supports the notion that Parkinson's disease (PD) may be caused by multiple factors and the result of "multiple hits" from environmental toxins.