Artikel
Beta amyloid mediated synaptic pathology in animal models of familial Alzheimer’s disease
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Veröffentlicht: | 11. September 2012 |
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Gliederung
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Alzheimer's disease (AD) is characterized by two main pathological hallmarks, extracellular deposits of beta amyloid and intracellular accumulation of hyperphosphorylated tau protein. Various pathogenetic mechanisms involving one or both of these alterations have been proposed, though the exact contribution of these mechanisms to the disease is unclear. As cognitive deficits in AD patients are most likely caused by an alteration and subsequent loss of synapses, we analysed the influence of fibrillar beta amyloid deposits on synaptic pathology in mouse models of familial Alzheimer's disease.
Computer based morphological analysis of immunohistochemically stained tissue sections revealed loss of PSD95-labelled glutamatergic postsynapses in the cortex, while synapsin-labelled presynapses were only minimally affected. However, in the close vicinity of methoxy-X04 labelled plaques (at distances up to ~20 µm), both pre- and postsynapses were reduced. Interestingly, presynapses were affected more strongly and at greater distances from plaques than postsynapses. These results suggest the presence of multiple varying pathogenetic mechanisms, which act at different distances from plaques and which affect pre- and postsynaptic structures differently.
In order to study the kinetics of synapse loss, we performed chronic vivo multiphoton imaging of Alzheimer transgenic mice, which also express sparsely fluorescently labelled neurons. Thus, we were able to simultaneously follow the kinetics of amyloid plaque deposition and dendritic spines, which are the morphological correlate of PSD95 bearing postsynapses. We observed that marked spine loss occurs only in the vicinity of plaques and lasts for months after the initial plaque formation. Furthermore, we observed that plaque formation always preceded spine loss. Thus, fibrillar beta amyloid causes loss of both pre- and postsynapses, which is most pronounced in close proximity to plaques.