, 2006) (Figure 6A). We used array tomography to allow high-resolution, quantitative measurement of synaptic densities. We found that both pre- and postsynaptic densities were significantly reduced in the middle third of the molecular layer at 24 months of age in tau-expressing transgenic mice (Figure 6B). To estimate neuronal loss, neuronal counts in the EC and hippocampal subareas were performed on transgenic and control animals at 21 and 24 months of age (n = 3 to 4 animals per group), using stereological estimations of cresyl violet-labeled neuronal nuclei. Neurons were identified by their morphology. In INCB018424 in vivo rTgTauEC mice, significant

neuronal loss was detected at 24 months of age in the areas of transgene expression, EC-II, and parasubiculum, compared to the average neuron number in age-matched control brains (Figure 6C). We observed a 42% decrease in neuron density in EC-II. We did not observe significant neuronal loss up to 21 months of age. Quantification by stereological counts showed that 47% of all neurons in the EC-II were Alz50-positive at 12 months

of age; this figure dropped to approximately 10% at 24 months of age (Figure 6D), as some neurons died. We hypothesize that the observed age-associated neurodegeneration is due to the age-dependent toxicity of tau that GSK126 research buy is pathologically mislocalized to the soma, hyperphosphorylated, and aggregated, similar to observations in human AD brain. To formally exclude the possibility that axonal degeneration and Phosphoprotein phosphatase neuronal loss

at 24 months are not due to increased transgene expression at later ages, we quantified the percentage of neurons expressing the human tau transgene. Stereological counts of human tau-expressing neurons labeled with FISH show that approximately 12% of neurons (12.4% ± 1.69% SEM) in EC-II expressed the transgene at 3 months of age (Figures 6E and 6F). This number was unchanged at 12 months (13.21% ± 0.86% SEM; p = 0.366) and 18 months of age (12.18% ± 1.96 SEM; p = 0.481), showing that only a portion of neurons in the EC-II expressed the human tau transgene. At 24 months of age, only ∼4% (3.71% ± 0.84% SEM) of the neurons expressed the transgene (Figures 1C and 1D) (p < 0.005). The pattern of human tau protein expression also changes as the animals age. There is a significant reduction in the human tau immunofluorescence staining of the EC at 24 months, and the cell bodies of the DG neurons become immunoreactive for human tau, suggesting that the protein is being transmitted (Figure S4). Together, these data indicate that neurodegeneration begins in this model of early AD with degeneration of axon terminals followed by loss of synapses and neurons.