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With the aging world population, the prevalence of aging-related disorders is on the rise. Diseases such as Alzheimer's, type 2 diabetes mellitus (T2DM), Parkinson's, atherosclerosis, hypertension, and osteoarthritis are age-related, and most of these diseases are comorbidities or risk factors for AD; however, our understandings of molecular events that regulate the occurrence of these diseases are still not fully understood. Brain and muscle Arnt-like protein-1 (Bmal1) is an irreplaceable clock gene that governs multiple important physiological processes. Continuous research of Bmal1 in AD and associated aging-related diseases is ongoing, and this review picks relevant studies on a detailed account of its role and mechanisms in these diseases. Oxidative stress and inflammation turned out to be common mechanisms by which Bmal1 deficiency promotes AD and associated aging-related diseases, and other Bmal1-dependent mechanisms remain to be identified. Promising therapeutic strategies involved in the regulation of Bmal1 are provided, including melatonin, natural compounds, metformin, d-Ser2-oxyntomodulin, and other interventions, such as exercise, time-restricted feeding, and adiponectin. The establishment of the signaling pathway network for Bmal1 in aging-related diseases will lead to advances in the comprehension of the molecular and cellular mechanisms, shedding light on novel treatments for aging-related diseases and promoting aging-associated brain health.

The circadian clock is an endogenous system designed to anticipate and adapt to daily changes in the environment. Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is more prevalent in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disruption on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (a 6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability, and AD-related pathophysiology. Our results indicated that housing in these conditions led to disrupted diurnal circadian rhythms in the hippocampus of db/db mice and contributed to their weight gain. In the brain, the circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in amyloid protein (Aβ) plaque deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under the 6:18 light/dark cycle. Circadian alterations could promote the development of AD in T2DM.

Jiaojiao Huang, Xuemin Peng, Kun Dong, Jing Tao, Yan Yang Department of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, People’s Republic of ChinaCorrespondence: Yan YangDepartment of Endocrinology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan, Hubei, 430030, People’s Republic of ChinaTel +86-27-83663331Fax +86-27-83662883Email yangyan6910@163.comAim: This study aimed to compare HOMA-IR, leptin, and resistin as the risk factors for diabetic nephropathy in the type 2 diabetes mellitus (T2DM) patients with different BMI classifications.Materials and Methods: A total of 309 patients with T2DM were enrolled in this cross-sectional study. All participants were divided into three groups according to BMI: the normal weight group (18.5 kg/m2≤BMI< 24 kg/m2), the overweight group (24kg/m2≤BMI< 28 kg/m2) and the obesity group (BMI≥ 28 kg/m2). The clinical information and laboratory examinations were recorded in detail. Leptin and resistin levels were measured using enzyme-linked immunosorbent assay (ELISA).Results: Higher HOMA-IR, leptin and resistin levels were found to be the risk factors for diabetic nephropathy when we made comparisons in the total population (P< 0.05). In the normal weight group, logistic regression analysis showed that T2DM patients with higher HOMA-IR (OR=4.210, P=0.001), leptin (OR=2.474, P=0.031) and resistin levels (OR=8.299, P< 0.001) had nearly 4-fold, 2-fold and 8-fold risk for diabetic nephropathy, respectively, after adjustments. The receiver operating characteristic (ROC) curves indicated that the area under the curves (AUCs) of HOMA-IR and resistin were 0.699 (95% CI 0.617– 0.772) and 0.790 (95% CI 0.715– 0.854), respectively, which were significantly larger than the AUC of 0.5 (all P< 0.001). However, no significant association was observed between HOMA-IR, leptin, and resistin and renal complications (all P> 0.05) in the overweight and obesity groups in both logistic regression and AUC analysis.Conclusion: Higher insulin resistance, leptin and resistin levels were observed as risk factors for diabetic nephropathy in T2DM patients with lower BMI. These were not obvious in the overweight and obese patients.Keywords: type 2 diabetes mellitus, insulin resistance, leptin, resistin, diabetic nephropathy

Introduction: Type 2 diabetes mellitus (T2DM) has a significantly increased risk of developing Alzheimer’s disease (AD). Amyloid-β (Aβ) as one of the main pathological features in AD increases in the brain of T2DM. A recent study identified a protective novel subset of microglial­ in AD—disease-associated microglia (DAM), the activation of which depends on TREM2(a myeloid cell membrane receptor) to phagocytose Aβ plaques. However, as to how T2DM increases Aβ deposition and the relationship between T2DM with DAM remain elusive. Objective: This study aims to explore the relationship between progression of T2DM with DAM and Aβ. Methods: In vivo experiment, the deposition of Aβ, inflammation as well as the phenotype of DAM were evaluated by RT-PCR and immunofluorescence in the cortex and hippocampus of 10-,15-,20-week old db/db mice and the age-matched WT control. Additionally, the effects of high insulin-induced insulin resistance (100nM) on the DAM signature markers and the production of inflammatory cytokines in BV-2 microglial cells were investigated in vitro. Results: We found the soluble and insoluble Aβ40, Aβ42, Aβ plaques as well as inflammation in the cortex and hippocampus increased in the progression of T2DM. Correspondingly, the DAM phenotype was reduced in the cortex and hippocampus at relatively early stage of T2DM (10 weeks and 15 weeks), while it increased reactively at the late stage (20 weeks). Likewise, high insulin-stimulated BV-2 microglial cells showed reduced Trem2 level and DAM signature markers and increase inflammation as well as Erk1/2 level. However, after the treatment of Erk1/2 inhibitor, the BV-2 cells under high insulin showed restored Trem2 level and DAM phenotype. Conclusion: T2DM brain has decreased DAM phenotype at a relatively early stage, which may explain the increased Aβ deposition. This may involve Erk1/2 -Trem2 signaling pathway, which could be a potential candidate especially at early stages for preventing T2DM-induced AD. Disclosure X. Peng: None. Funding National Natural Science Foundation of China (81974114)

The circadian clock is an endogenous system designed to anticipate and adapt to daily changes in the environment. Alzheimer's disease (AD) is a progressive neurodegenerative disease, which is more prevalent in patients with type 2 diabetes mellitus (T2DM). However, the effects of circadian disruption on mental and physical health for T2DM patients are not yet fully understood, even though circadian disruption has been confirmed to promote the progression of AD in population. By housing db/db mice on a disrupted (a 6:18 light/dark cycle) circadian rhythm, we assessed the circadian gene expression, body weight, cognitive ability, and AD-related pathophysiology. Our results indicated that housing in these conditions led to disrupted diurnal circadian rhythms in the hippocampus of db/db mice and contributed to their weight gain. In the brain, the circadian-disrupted db/db mice showed a decreased cognitive ability and an increased hyperphosphorylation of tau protein, even though no difference was found in amyloid protein (Aβ) plaque deposition. We also found that the hyperphosphorylated tau protein exhibited more disruptive daily oscillations in db/db mice hippocampus under the 6:18 light/dark cycle. Circadian alterations could promote the development of AD in T2DM.

Aeolian deposits (including aeolian sands and loess deposits) are widely distributed in the Poyang Lake region located in the middle reaches of the Yangtze River. The chronology and provenance, and their environmental implications, of these aeolian sediments have been debated for decades. Based on the OSL chronology, sedimentology, grain size analysis, and elementary data, we conclude that: (1) The source materials for the aeolian sediments in the Poyang Lake region originated from the local flood plains of the Yangtze River and its tributary Ganjiang River, whose fine materials were transported by the strong northwestern winter monsoon wind. (2) Aeolian deposits occurred throughout Late Pleistocene. Loess has a timing interval of 160–25 ka, concentrating in 115–50 ka. Sand accumulated as early as 115 ka, actively occurred during 85–80 ka. (3) Compared with the channel of the Yangtze River of today, the channel was further to the north before 80–85 ka in the Last Interglaciation, and shifted southward afterward.