Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Abstract

Although there is evidence that β-amyloid impairs synaptic function, the relationship between β-amyloid and synapse loss is not well understood. In this study, we assessed synapse density within the hippocampus and the entorhinal cortex of Tg2576 mice at 6-18 months of age using stereological methods at both the light and electron microscope levels. Under light microscopy, we failed to find overall decreases in the density of synaptophysin-positive boutons in any brain areas selected, but bouton density was significantly decreased within 200 μm of compact β-amyloid plaques in the outer molecular layer of the dentate gyrus and layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. Under electron microscopy, we found overall decreases in synapse density in the outer molecular layer of the dentate gyrus at both 6-9 and 15-18 months of age, and in layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. However, we did not find overall changes in synapse density in the stratum radiatum of the CA1 subfield. Furthermore, in the two former brain areas, we found a correlation between lower synapse density and greater proximity to β-amyloid plaques. These results provide the first quantitative morphological evidence at the ultrastructure level of a spatial relationship between β-amyloid plaques and synapse loss within the hippocampus and the entorhinal cortex of Tg2576 mice.

PKC ε Activation Prevents Synaptic Loss, Aβ Elevation, and Cognitive Deficits in Alzheimer's Disease Transgenic Mice

“…4C-E) results demonstrated that the decrease in PKC protein level in the hippocampal CA1 area of Tg2576 mice was the result of the decreased numbers of presynaptic boutons that contained PKC rather than a result of decreased PKC levels in the individual boutons. A previous study, for another example, demonstrated that the number of total synapses was not changed in CA1 stratum radiatum (Dong et al, 2007), whereas our results demonstrate a significant decrease in the synapses per unit volume of CA1 stratum radiatum.…”

Place cell firing correlates with memory deficits and amyloid plaque burden in Tg2576 Alzheimer mouse model

“…Accumulating evidence points to the in vivo toxicity of compact amyloid plaques. Dong et al (22) observed a selective loss of dendritic synapses occurring in the proximity of amyloid plaques in the entorhinal cortex and the outer molecular layer of the dentate gyrus of aged Tg2576 mice (22). Indeed, amyloid plaques are selectively associated with dystrophic neurites in these mice (23), and such deposits have been associated with local structural disruption of synapses and breakage of neuronal branches (24).…”

Effects of Memantine on Neuronal Structure and Conditioned Fear in the Tg2576 Mouse Model of Alzheimer's Disease

“…The molecular layer of the dentate gyrus is one of the first regions to show amyloid deposition and synapse loss in the Tg2576 mouse model of AD (Su and Ni, 1998;Reilly et al, 2003;Dong et al, 2007). However, it is difficult to know the implications of increases in synapse density after memantine administration in Tg2576 mice.…”

“…Degenerating axons were identified on photographs by the presence of vesicular and lamellar debris within the atrophic axon. A stereological dissector technique was used to measure the density of synapses and degenerating axons (West and Gundersen, 1990;Geinisman et al, 2000;Dong et al, 2007). Each dissector consisted of micrographs of two adjacent ultrathin sections, a reference section and a look-up section immediately above it.…”