Correlation of protein tau and amyloid beta aggregates neuroinflammation and oxidative stress in 5xFAD and P301S mice

Abstract

AbstractBackgroundThe deposition of protein tau (Tau) and amyloid beta (Aβ) aggregates during Alzheimer disease (AD) is accompanied by other processes, mostly controlled by glial activation. Despite numerous attempts, there is little information on the role of these processes in the disease mechanism. Exact mapping and correlation of pathological changes would give information that could help reveal underlying causes for the onset of the disease. We set off to longitudinally investigate and correlate disease related processes in the brains of 5xFAD and P301S mice models.MethodNeuroinflammation and oxidative stress in P301S and 5xFAD transgenic (tg) mice were monitored longitudinally by PET‐CT imaging and compared to age‐matched healthy controls (WT). PET imaging using [18F]DPA‐714, [18F]FSPG, [18F]florbetaben, and [18F]EFAPEM1 was performed to assess levels of neuroinflammation, oxidative stress, Aβ load (5xFAD mice) and Tau aggregates (P301S) load, respectively. Uptake in the cortex (CTX) was presented as SUV or SUVr when a reference region was available. IHC staining of brain slices for Aβ, Tau deposits, neuroinflammation and oxidative stress is currently in progress.ResultPET‐CT studies showed increase of levels of Tau deposits at 8 month‐old P301S mice and Aβ levels at 6, 8 and 10 month‐old 5xFAD mice. For 5xFAD mice, [18F]DPA‐714 and [18F]FSPG uptake followed the trend of Aβ deposition, peaking at 8 months. Compared to WT mice, four‐fold increase in [18F]DPA‐714 (p<0.0001) and three‐fold increase in [18F]FSPG (p=0.0019) SUV was observed, suggesting protein deposits‐induced increase in inflammation and oxidative stress. Surprisingly, neuroinflammation and oxidative stress did not follow the trend of Tau deposition in P301S mice.ConclusionLongitudinal deposition of Aβ and Tau was in accordance with reported ex vivo data for the two animal models. Neuroinflammation and oxidative stress correspond well with the levels of Aβ, longitudinally. The two processes also occur in P301S mice brain but correspond poorly with Tau deposition. These results suggest that either Aβ and Tau aggregates affect neuroinflammation and oxidative stress differently, or that neuroinflammation and oxidative stress are independent processes. Further studies are in progress to confirm the observed data.