ABSTRACT
Aggregates of amyloid-beta (Aß) and tau are hallmarks of Alzheimer's disease (AD) leading to neurodegeneration and synaptic loss. While increasing evidence suggests that inhibition of N-methyl-D-aspartate receptors (NMDARs) may mitigate certain aspects of AD neuropathology, the precise role of different NMDAR subtypes for Aß- and tau-mediated toxicity remains to be elucidated. Using mouse organotypic hippocampal slice cultures from arcAß transgenic mice combined with Sindbis virus-mediated expression of human wild-type tau protein (hTau), we show that Aß caused dendritic spine loss independently of tau. However, the presence of hTau was required for Aß-induced cell death accompanied by increased hTau phosphorylation. Inhibition of NR2B-containing NMDARs abolished Aß-induced hTau phosphorylation and toxicity by preventing GSK-3ß activation but did not affect dendritic spine loss. Inversely, NR2A-containing NMDAR inhibition as well as NR2A-subunit knockout diminished dendritic spine loss but not the Aß effect on hTau. Activation of extrasynaptic NMDARs in primary neurons caused degeneration of hTau-expressing neurons, which could be prevented by NR2B-NMDAR inhibition but not by NR2A knockout. Furthermore, caspase-3 activity was increased in arcAß transgenic cultures. Activity was reduced by NR2A knockout but not by NR2B inhibition. Accordingly, caspase-3 inhibition abolished spine loss but not hTau-dependent toxicity in arcAß transgenic slice cultures. Our data show that Aß induces dendritic spine loss via a pathway involving NR2A-containing NMDARs and active caspase-3 whereas activation of eSyn NR2B-containing NMDARs is required for hTau-dependent neurodegeneration, independent of caspase-3.
Subject(s)
Amyloid beta-Peptides/metabolism , Dendritic Spines/metabolism , Hippocampus/metabolism , Neurons/metabolism , Receptors, N-Methyl-D-Aspartate/metabolism , Amyloid beta-Peptides/genetics , Animals , Apoptosis , Caspase 3/metabolism , Cells, Cultured , Glycogen Synthase Kinase 3/metabolism , Glycogen Synthase Kinase 3 beta , Hippocampus/cytology , Humans , In Vitro Techniques , Mice , Mice, Knockout , Mice, Transgenic , Neurons/cytology , Phosphorylation , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/genetics , tau Proteins/genetics , tau Proteins/metabolismABSTRACT
BACKGROUND: Based on the dermoscopic classification of acquired melanocytic naevi, six different dermoscopic types can be distinguished by morphology (globular, globular-reticular, globular-homogeneous, reticular, reticular-homogeneous, homogeneous) and by pigment distribution (uniform, central hyperpigmentation, central hypopigmentation, peripheral hyperpigmentation, peripheral hypopigmentation, multifocal hyper/hypopigmentation). It has been suggested that most individuals harbour one predominant dermoscopic type among their naevi. OBJECTIVES: To evaluate whether the age of the patient influences the predominant naevus pattern observed in individuals with multiple acquired melanocytic naevi. METHODS: Individuals were recruited from the pigmented skin lesion clinic in Graz between July 2000 and February 2001. Individuals with at least 10 melanocytic naevi were selected consecutively until a total of 10 individuals in each of five age groups was obtained. Age groups were: 0-15 years, 16-30 years, 31-45 years, 46-60 years and > 60 years. Digitized images of acquired melanocytic naevi, defined as benign melanocytic proliferations having a diameter of at least 5 mm with a macular component and which were not apparent within the first year of life, were evaluated by dermoscopic criteria. The associations of dermoscopic features as a function of patient age were analysed. We calculated absolute numbers and frequencies, given as percentages, as well as predominance of the dermoscopic types of naevi in the different age groups. RESULTS: Analysis of 1268 naevi revealed that the globular pattern predominated in the youngest age group. By contrast, the reticular and/or homogeneous patterns were increasingly exhibited in naevi from older individuals (older than 15 years). Uniform pigmentation was most common in melanocytic naevi in the youngest age group, while central hyperpigmentation was predominantly seen in the group of individuals aged 16-30 years. CONCLUSIONS: The predominance of dermoscopic types of melanocytic naevi varies according to the individual's age. Awareness of the age-related dermoscopic predominance of melanocytic naevi might allow more accurate recognition of dermoscopic patterns of melanocytic skin lesions that are unusual with respect to the individual's age. This observation may help in the early recognition of some 'banal'-appearing melanomas. Furthermore, the observations made in this study raise interesting questions regarding naevus evolution.
