Characterization of preclinical Alzheimer's disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology.

BACKGROUND: The key to the prevention and treatment of Alzheimer's disease (AD) is to be able to predict and diagnose AD at the preclinical or early stage, but the lack of a preclinical model of AD is the critical factor that causes this problem to remain unresolved. METHODS: We assessed 18 monkeys in vivo evaluation of pro-inflammatory cytokines and AD pathological biomarkers (n = 9 / type 2 diabetic mellitus (T2DM) group, age 20, fasting plasma glucose (FPG) ≥ 100 mg/dL, and n = 9 / negative control (NC) group, age 17, FPG < 100 mg/dL). Levels of pro-inflammatory cytokines and AD pathological biomarkers was measured by ELISA and Simoa Technology, respectively. 9 monkeys evaluated ex vivo for AD-like pathology (n = 6 / T2DM group, age 22.17, FPG ≥ 126 mg/dL, and n = 3 / NC group, age 14.67, FPG < 100 mg/dL). To evaluate the pathological features of AD in the brains of T2DM monkeys, we assessed the levels of Aß, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Aß plaques by Bielschowsky's silver, Congo red, and Thioflavin S staining. Synaptic damage and neurodegeneration were assessed by immunofluorescence. RESULTS: We found not only increased levels of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased ß-amyloid (Aß) 42 and Aß40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Aß plaque deposition, p-tau from neuropil thread to pre-neurofibrillary tangles (NFTs), and even the appearance of extracellular NFT. Microglia were activated from a resting state to an amoeboid. Astrocytes showed marked hypertrophy and an increased number of cell bodies and protrusions. Finally, we observed impairment of the postsynaptic membrane but no neurodegeneration or neuronal death. CONCLUSIONS: Overall, T2DM monkeys showed elevated levels of peripheral and intracerebral inflammation, positive AD biomarkers in body fluids, and developing AD-like pathology in the brain, including Aß and tau pathology, glial cell activation, and partial synaptic damage, but no neuronal degeneration or death as compared to the healthy normal group. Hereby, we consider the T2DM monkeys with elevation of the peripheral pro-inflammatory factors and positive AD biomarkers can be potentially regarded as a preclinical AD model.

Eco-exergy and emergy based self-organization of three forest plantations in lower subtropical China.

The bio-thermodynamic structures of a mixed native species plantation, a conifer plantation and an Acacia mangium plantation in Southern China were quantified over a period of 15 years based on eco-exergy methods. The efficiencies of structural development and maintenance were quantified through an integrated application of eco-exergy and emergy methods. The results showed that the storage of eco-exergy increased over 3 times in all three plantations, as predicted by the maximum eco-exergy principle. This trend was primarily seen due to the accumulation of biomass, instead of an increase in the specific eco-exergy (eco-exergy per unit biomass), although species richness did increase. The eco-exergy to emergy and eco-exergy to empower ratios of the three plantations generally increased during the study period, but the rate of increase slowed down after 20 years. The dominant trees are the largest contributors to the eco-exergy stored in the plantations, and thus, the introduction of suitable indigenous tree species should be considered after the existing trees pass through their period of most rapid growth or around 20 years after planting. The combined application of C-values and suggested weighting factors in the eco-exergy calculation can imply opposite results, but may also supply useful information for forest management.