Insulin resistance as a hallmark of type 2 DM (T2DM) plays a role in dementia by promoting pathological lesions or enhancing the vulnerability of the brain. Numerous studies related to insulin/insulin-like growth factor 1 (IGF-1) signaling are linked with various types of dementia. Brain insulin resistance in dementia is linked to disturbances in Aβ production and clearance, Tau hyperphosphorylation, microglial activation causing increased neuroinflammation, and the breakdown of tight junctions in the blood-brain barrier (BBB). These mechanisms have been studied primarily in Alzheimer's disease (AD), but research on other forms of dementia like vascular dementia (VaD), Lewy body dementia (LBD), and frontotemporal dementia (FTD) has also explored overlapping mechanisms. Researchers are currently trying to repurpose anti-diabetic drugs to treat dementia, which are dominated by insulin sensitizers and insulin substrates. Although it seems promising and feasible, none of the trials have succeeded in ameliorating cognitive decline in late-onset dementia. We highlight the possibility of repositioning anti-diabetic drugs as a strategy for dementia therapy by reflecting on current and previous clinical trials. We also describe the molecular perspectives of various types of dementia through the insulin/IGF-1 signaling pathway.
Recent evidence indicates brain ischemia is associated with accumulations of abnormal tau and related proteins. However, the effects of aerobic training on these proteins have not been evaluated.We aimed to evaluate the effect of aerobic exercise on the phosphorylation and acetylation of tau and on the expressions of tau related proteins in a rat stroke model and to compare the effects of aerobic exercise with those observed in our previous study on task specific training (TST).Twenty-four Sprague- Dawley rats with photothrombotic cortical infarction were used in the current study. The rehabilitation group (RG) received treadmill training 40 min/day for 28 days, whereas the sedentary group (SG) did not receive any type of training. Functional tests such as the single pellet reaching task, rotarod, and radial arm maze tests were performed weekly for 4 weeks post-infarction.Levels of p-taus396 and p-AMPK were found to be lower in ipsilateral cortices in the RG than in the SG (p < 0.05). Levels of p-taus262, Ac-tau, p-GSK3βS9, p-Akt, p-Sin1, and p-P70-S6K were significantly lower in ipsilateral than in contralateral cortices in the RG (p < 0.05). Aerobic training also improved motor, balance, and memory functions.Aerobic training inhibited the phosphorylation and acetylation of tau and modulated the expressions of tau related proteins after stroke by modifying the p70-S6K pathway and p-AMPK. By comparison with our previous study on the effects of TST, we have evidence to suggest that TST and aerobic exercise differ, although both types of rehabilitation inhibit tau phosphorylation and acetylation.
Abstract Background Roles for extracellular vesicles (EVs) enriched with micro-RNAs (miRNAs) have been proposed in Alzheimer’s disease (AD) pathogenesis, leading to the discovery of blood miRNAs as AD biomarkers. However, the diagnostic utility of specific miRNAs is not consistent. This study aimed to discover blood miRNAs that are differentially expressed in Korean AD patients, evaluate their clinical performance, and investigate their role in amyloidogenesis. Methods We discovered miRNAs differentially expressed in AD (N = 8) from cognitively normal participants (CN, N = 7) or Parkinson’s disease (PD) patients (N = 8). We evaluated the clinical performance of these miRNAs in plasma of subgroup (N = 99) and in plasma EVs isolated from the total cohort (N = 251). The effects of miRNAs on amyloidogenesis and on the regulation of their target genes were investigated in vitro. Results Among 17 upregulated and one downregulated miRNAs in AD (>twofold), miR-122-5p, miR-210-3p, and miR-590-5p were differentially expressed compared with CN or PD. However, the diagnostic performance of the selected plasma or EV miRNAs in total participants were limited (area under the curve < 0.8). Nevertheless, levels of 3 miRNAs in plasma or plasma EVs of participants who were amyloid positron emission tomography (Aβ-PET) positive were significantly higher than those from the Aβ-PET negative participants (p < .05). The selected miRNAs induced Aβ production (p < .05) through activation of β-cleavage of amyloid precursor protein (CTF-β; p < .01), and downregulated their target genes (ADAM metallopeptidase domain 10, Brain-derived neurotrophic factor, and Jagged canonical notch ligand 1; p < .05), which was further supported by pathway enrichment analysis of target genes of the miRNAs. Conclusion In conclusion, despite of the limited diagnostic utility of selected miRNAs as plasma or plasma EV biomarkers, the discovered miRNAs may play a role in amyloidogenesis during AD onset and progression.
The complicated differentiation processes of cells in skeletal muscle against inflammation that induce muscle atrophy are not fully elucidated. Given that skeletal muscle is a secretory organ, we evaluated the effects of inflammation on myogenic signals and myokine expression, and the roles of inflammatory exosomes released by myotubes in myogenic differentiation.Inflammation was induced by treatment of fully differentiated C2C12 myotubes with a cytokine mixture of TNF-α and INF-γ. Exosome-like vesicles (ELVs) were isolated from conditioned media of control or inflamed myotubes and incubated with myoblasts. The expression of molecular switches that contribute to myogenic differentiation, including several kinases, their downstream targets, and myokines, were evaluated using immunoblot analysis in inflamed myotubes and in myoblasts treated with ELVs.Inflammation activated molecular mechanisms contributing to muscle atrophy, including AMPK, p-38 MAPK and JNK, while inhibiting Akt-mediated myogenic signals. In addition, inflammation induced myostatin expression with suppression of a myostatin-counteracting myokine, decorin. Well-characterized ELVs released from inflamed myotubes induced myoblast inflammation and inhibited myogenic mechanisms while stimulating atrophic signals.Inflammation of skeletal muscle induces muscle atrophy via multiple mechanisms, including the regulation of myokines and kinases. Inflammatory ELVs are likely to contribute to inflammation-induced muscle atrophy.
Exosome-like extracellular vesicles (ELVs) contain biomolecules that have potential as diagnostic biomarkers, such as proteins, micro-RNAs (miRNAs), and lipids. However, it is difficult to enrich ELVs consistently with high yield and purity from clinical samples, which hampers the development of ELV biomarkers. This is particularly true for miRNAs in protein-rich plasma. Hence, we modified ELV isolation protocols of three commercially available polymer-precipitation-based kits using proteinase K (PK) treatment to quantify ELV-associated miRNAs in human plasma. We compared the yield, purity, and characteristics of enriched plasma ELVs, and measured the relative quantity of three selected miRNAs (miR-30c, miR-126, and miR-192) in ELVs using six human plasma samples. Compared with the original protocols, we demonstrated that ELVs can be isolated with PK treatment with high purity (i.e., lack of non-exosomal proteins and homogeneous size of vesicles) and yield (i.e., abundancy of exosomal markers), which were dependent on kits. Using the kit with the highest purity and yield with PK treatment, we successfully quantified ELV miRNAs (levels of 45%-65% in total plasma) with acceptable variability. Collectively, ELV enrichment using the modified easy-to-use method appears suitable for the analysis of miRNAs, although its clinical applicability needs to be confirmed in larger clinical studies.
Although stroke elicits progressive cognitive decline and is a major cause of dementia, molecular interplay between stroke and Alzheimer's disease (AD) pathology has not been fully elucidated. Furthermore, studies on the effects of post-stroke rehabilitation on AD pathology are limited. The care of animals and a protocol approved by the Institutional Animal Care and Handling Committee. Sprague-Dawley rats were randomly assigned to rehabilitation group (RG) and sedentary control group (SC) following photothrombotic infarction in the dominant side of sensorimotor cortex. RG received 4-weeks of task-specific rehabilitation once daily by single pellet reaching training (SPRT). Cortical expression levels of proteins related to tau modification and inflammation were evaluated on post-stroke day (PSD) 1 and 28. The expression levels of acetyl-tau, phosphorylated-tau at Ser262(p-tauS262) and Ser202/Thr205 (p-tau202/205) and truncated tau on PSD1 were significantly higher in infarcted cortex (ipsilateral) than the paired non-ischemic cortex (contralateral), whereas p-tauS396 levels was comparable. The positive feedback loop of Akt-mTORC2 (p-Sin1) and concurrent activation of mTORC1-p70S6K pathway in ipsilateral sides on PSD1 were significantly greater, whereas the expression levels of p-AMPK, GSK3β activity, Sirt1 and brain-derived neurotrophic factor were significantly lower than in the paired contralateral sides. The acute increase of cyclooxygenase 2 (COX-2) levels was also observed. The rehabilitation by SPRT for 4 weeks significantly attenuated the tau phosphorylation and activation of Akt-mTORC1-p70S6K pathway in ipsilateral cortex of RG, as compared to those in ipsilateral cortex of SC, which concurred with improvement of functional motor performance but not memory. In addition, the levels of ipsilateral p-AMPK and COX-2 of RG was significantly lower than those of SC, whereas the ipsilateral GSK3β activity and acetyl tau levels of RG were comparable to those of SC. Photothrombotic cortical infarction was found to induce cortical tau modification through the Akt-mTORC1-p70S6K activation, and to downregulate the expression of AMPK-related proteins. Task-specific rehabilitation for 4 weeks greatly improved motor function, but not memory, and suppressed p-tau expression and neuroinflammation. These results indicated that rehabilitation training may attenuate the acute pathologic changes related to tau modification and inflammation after cortical ischemic damage.
Sarcopenia has been defined as a progressive decline of skeletal muscle mass, strength, and functions in elderly people. It is accompanied by physical frailty, functional disability, falls, hospitalization, and mortality, and is becoming a major geriatric disorder owing to the increasing life expectancy and growing older population worldwide. Experimental models are critical to understand the pathophysiology of sarcopenia and develop therapeutic strategies. Although its etiologies remain to be further elucidated, several mechanisms of sarcopenia have been identified, including cellular senescence, proteostasis imbalance, oxidative stress, and "inflammaging." In this article, we address three main aspects. First, we describe the fundamental aging mechanisms. Next, we discuss both in vitro and in vivo experimental models based on molecular mechanisms that have the potential to elucidate the biochemical processes integral to sarcopenia. The use of appropriate models to reflect sarcopenia and/or its underlying pathways will enable researchers to understand sarcopenia and develop novel therapeutic strategies for sarcopenia. Lastly, we discuss the possible molecular targets and the current status of drug candidates for sarcopenia treatment. In conclusion, the development of experimental models for sarcopenia is essential to discover molecular targets that are valuable as biochemical biomarkers and/or therapeutic targets for sarcopenia.
Abstract Background: Universal Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker cutoffs from immunoassays with low interlaboratory variability could improve diagnostic accuracy and help predict disease progression. To determine the diagnostic cutoffs of CSF AD biomarkers measured with three immunoassay platforms, including fully automated Lumipulse based on b-amyloid (Ab) positron emission tomography (PET) status, to determine diagnostic utility and clinical predictability. Methods: Three hundred thirty-one Korean participants were enrolled from a prospective, 3-year longitudinal observational study of the validation cohort of Korean Brain Aging Study for the Early Diagnosis and Prediction of AD: 71 cognitively normal (CN), 99 with subjective cognitive decline (SCD), 89 with mild cognitive impairment (MCI), and 72 with AD. Among these 331 participants, 139 (29, 58, 29, and 23 from each group, respectively) provided CSF and 271 underwent baseline amyloid PET. Three annual cognitive and neuropsychiatric function tests were conducted. Ab42, Ab40, total-tau and phosphorylated-tau 181 were measured by Lumipulse fully automated immunoassay and two manual immunoassays (INNO-BIA AlzBio3, INNOTEST). Clinical utility of CSF biomarker cutoffs, based on 128 participants with Ab-PET, were evaluated. Results: Cognitive and neuropsychological scores differed significantly among the groups, with descending performance among CN > SCD > MCI > AD. Biomarker levels among immunoassays were strongly intercorrelated, and using the cutoffs for Ab-PET status with maximal AD diagnostic accuracy (n = 215), the levels showed excellent agreement with Ab-PET. Use of Ab-PET-based cutoffs for CSF biomarkers showed excellent diagnostic discrimination between AD and CN (Ab42, Ab42/Ab40, t-tau/Ab42 and p-tau/Ab42) with overall AUC ranges to discriminate AD and CN (0.876–0.952). During follow-up, participants with AD-like CSF signature determined by Ab-PET-based cutoffs from Lumipulse showed rapid progression of clinical scores, after adjustment for potential confounders, compared with those with a normal CSF signature. Conclusion: CSF AD biomarkers measured by different immunoassay platforms show strong intercorrelated agreement with Ab-PET. Ab-PET-based CSF biomarker cutoffs measured by immunoassays, including the Lumipulse, strongly predict progression of cognitive decline. The clinical utility of CSF biomarkers from fully automated immunoassay platforms should be evaluated in larger, more diverse cohorts.
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