PMID- 38459540 OWN - NLM STAT- MEDLINE DCOM- 20240311 LR - 20240312 IS - 1758-9193 (Electronic) VI - 16 IP - 1 DP - 2024 Mar 8 TI - Characterization of preclinical Alzheimer's disease model: spontaneous type 2 diabetic cynomolgus monkeys with systemic pro-inflammation, positive biomarkers and developing AD-like pathology. PG - 52 LID - 10.1186/s13195-024-01416-9 [doi] LID - 52 AB - 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 Abeta, phospho-tau, and neuroinflammation using immunohistochemistry, which further confirmed the deposition of Abeta 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-alpha (TNF-alpha) in peripheral blood (PB) and brain of T2DM monkeys but also changes in PB of AD pathological biomarkers such as decreased beta-amyloid (Abeta) 42 and Abeta40 levels. Most notably, we observed AD-like pathological features in the brain of T2DM monkeys, including Abeta 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 Abeta 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. CI - (c) 2024. The Author(s). FAU - Huang, Xinxin AU - Huang X AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. FAU - Huang, Shanshan AU - Huang S AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. FAU - Fu, Fangyan AU - Fu F AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. FAU - Song, Junzhen AU - Song J AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. FAU - Zhang, Yuling AU - Zhang Y AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. FAU - Yue, Feng AU - Yue F AD - State Key Laboratory of Digital Medical Engineering, School of Biomedical Engineering, Hainan University, Sanya, 572025, China. fyuee@hotmail.com. AD - Collaborative Innovation Center of One Health, Hainan University, Hainan University, Haikou, 570228, China. fyuee@hotmail.com. LA - eng GR - 2021ZD0200900/STI2030-Major Projects/ GR - 2018YFA0108503/National Key Research and Development Program of China/ GR - ZDYF2021SHFZ049/National Hainan Key Research and Development Project/ GR - 322RC588/Hainan Province Natural Science Foundation of high-level talent project/ PT - Journal Article DEP - 20240308 PL - England TA - Alzheimers Res Ther JT - Alzheimer's research & therapy JID - 101511643 RN - 0 (Amyloid beta-Peptides) RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (tau Proteins) SB - IM MH - Animals MH - *Alzheimer Disease/pathology MH - Macaca fascicularis/metabolism MH - Amyloid beta-Peptides/metabolism MH - Inflammation/pathology MH - Brain/metabolism MH - Biomarkers MH - *Diabetes Mellitus, Type 2/complications MH - Cytokines/metabolism MH - tau Proteins/metabolism PMC - PMC10921774 OTO - NOTNLM OT - Alzheimer's disease OT - Biomarkers OT - Cynomolgus monkeys OT - Preclinical OT - Pro-inflammatory factor OT - Type 2 diabetes mellitus COIS- The authors declare no competing interests. EDAT- 2024/03/09 10:44 MHDA- 2024/03/11 06:44 PMCR- 2024/03/08 CRDT- 2024/03/08 23:52 PHST- 2023/11/22 00:00 [received] PHST- 2024/02/19 00:00 [accepted] PHST- 2024/03/11 06:44 [medline] PHST- 2024/03/09 10:44 [pubmed] PHST- 2024/03/08 23:52 [entrez] PHST- 2024/03/08 00:00 [pmc-release] AID - 10.1186/s13195-024-01416-9 [pii] AID - 1416 [pii] AID - 10.1186/s13195-024-01416-9 [doi] PST - epublish SO - Alzheimers Res Ther. 2024 Mar 8;16(1):52. doi: 10.1186/s13195-024-01416-9.