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1. Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells

   https://doi.org/10.3390/cells11030373  

   Jang, Sehwan; Chapa-Dubocq, Xavier R.; Parodi-Rullán, Rebecca M.; Fossati, Silvia; Javadov, Sabzali (February 2022, Cells)

   Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells. 

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2. TERMIS AM

   Yeoheung Yun, Balqees Khader (April 2023, Three-dimensional Alzheimer's disease's spheroid grafted neurovascular unit)

   Alzheimer’s disease (AD) is characterized by distinct tissue changes associated with accumulation of extracellular amyloid-beta (Aβ) peptides, and intracellular deposits of phosphorylated Tau (p-tau). There is a clear need to develop 3D AD model for alternative to animal test since current rodent model does not recapitulate complex human AD physiopathology. Here we report on organoid-grafted neurovascular unit (NUV) using 1) spheroid using APP-mutated neuro-progenitor cell and 2) endothelial-based blood brain barrier (BBB) against extracellular matrix. The construct was validated with AD pathology generation and further treatment with β- or γ-secretase inhibitors shows the decrease of Aβ. This paper demonstrates the potential utility of a membrane-free in vitro cortical spheroid tissue construct with BBB in a high throughput platform to model AD. 

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3. Initiation of Continuous Glucose Monitoring Is Linked to Improved Glycemic Control and Fewer Clinical Events in Type 1 and Type 2 Diabetes in the Veterans Health Administration

   https://doi.org/10.2337/dc22-2189  

   Reaven, Peter D.; Newell, Michelle; Rivas, Salvador; Zhou, Xinkai; Norman, Gregory J.; Zhou, Jin J. (February 2023, Diabetes Care)

   OBJECTIVETo determine the benefit of starting continuous glucose monitoring (CGM) in adult-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) with regard to longer-term glucose control and serious clinical events. RESEARCH DESIGN AND METHODSA retrospective observational cohort study within the Veterans Affairs Health Care System was used to compare glucose control and hypoglycemia- or hyperglycemia-related admission to an emergency room or hospital and all-cause hospitalization between propensity score overlap weighted initiators of CGM and nonusers over 12 months. RESULTSCGM users receiving insulin (n = 5,015 with T1D and n = 15,706 with T2D) and similar numbers of nonusers were identified from 1 January 2015 to 31 December 2020. Declines in HbA1c were significantly greater in CGM users with T1D (−0.26%; 95% CI −0.33, −0.19%) and T2D (−0.35%; 95% CI −0.40, −0.31%) than in nonusers at 12 months. Percentages of patients achieving HbA1c <8 and <9% after 12 months were greater in CGM users. In T1D, CGM initiation was associated with significantly reduced risk of hypoglycemia (hazard ratio [HR] 0.69; 95% CI 0.48, 0.98) and all-cause hospitalization (HR 0.75; 95% CI 0.63, 0.90). In patients with T2D, there was a reduction in risk of hyperglycemia in CGM users (HR 0.87; 95% CI 0.77, 0.99) and all-cause hospitalization (HR 0.89; 95% CI 0.83, 0.97). Several subgroups (based on baseline age, HbA1c, hypoglycemic risk, or follow-up CGM use) had even greater responses. CONCLUSIONSIn a large national cohort, initiation of CGM was associated with sustained improvement in HbA1c in patients with later-onset T1D and patients with T2D using insulin. This was accompanied by a clear pattern of reduced risk of admission to an emergency room or hospital for hypoglycemia or hyperglycemia and of all-cause hospitalization. 

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4. Repurposing of intestinal defensins as multi-target, dual-function amyloid inhibitors via cross-seeding

   https://doi.org/10.1039/D2SC01447E  

   Tang, Yijing; Zhang, Dong; Gong, Xiong; Zheng, Jie (June 2022, Chemical Science)

   Amyloid formation and microbial infection are the two common pathological causes of neurogenerative diseases, including Alzheimer's disease (AD), type II diabetes (T2D), and medullary thyroid carcinoma (MTC). While significant efforts have been made to develop different prevention strategies and preclinical hits for these diseases, conventional design strategies of amyloid inhibitors are mostly limited to either a single prevention mechanism (amyloid cascade vs. microbial infection) or a single amyloid protein (Aβ, hIAPP, or hCT), which has prevented the launch of any successful drug on the market. Here, we propose and demonstrate a new “anti-amyloid and anti-bacteria” strategy to repurpose two intestinal defensins, human α-defensin 6 (HD-6) and human β-defensin 1 (HBD-1), as multiple-target, dual-function, amyloid inhibitors. Both HD-6 and HBD-1 can cross-seed with three amyloid peptides, Aβ (associated with AD), hIAPP (associated with T2D), and hCT (associated with MTC), to prevent their aggregation towards amyloid fibrils from monomers and oligomers, rescue SH-SY5Y and RIN-m5F cells from amyloid-induced cytotoxicity, and retain their original antimicrobial activity against four common bacterial strains at sub-stoichiometric concentrations. Such sequence-independent anti-amyloid and anti-bacterial functions of intestinal defensins mainly stem from their cross-interactions with amyloid proteins through amyloid-like mimicry of β-sheet associations. In a broader view, this work provides a new out-of-the-box thinking to search and repurpose a huge source of antimicrobial peptides as amyloid inhibitors, allowing the blocking of the two interlinked pathological pathways and bidirectional communication between the central nervous system and intestines via the gut–brain axis associated with neurodegenerative diseases. 

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5. Conformational-specific self-assembled peptides as dual-mode, multi-target inhibitors and detectors for different amyloid proteins

   https://doi.org/10.1039/D1TB02775A  

   Ren, Baiping; Tang, Yijing; Zhang, Dong; Liu, Yonglan; Zhang, Yanxian; Chen, Hong; Hu, Rundong; Zhang, Mingzhen; Zheng, Jie (March 2022, Journal of Materials Chemistry B)

   Prevention and detection of misfolded amyloid proteins and their β-structure-rich aggregates are the two promising but different (pre)clinical strategies to treat and diagnose neurodegenerative diseases including Alzheimer's diseases (AD) and type II diabetes (T2D). Conventional strategies prevent the design of new pharmaceutical molecules with both amyloid inhibition and detection functions. Here, we propose a “like-interacts-like” design principle to de novo design a series of new self-assembling peptides (SAPs), enabling them to specifically and strongly interact with conformationally similar β-sheet motifs of Aβ (association with AD) and hIAPP (association with T2D). Collective in vitro experimental data from thioflavin (ThT), atomic force microscopy (AFM), circular dichroism (CD), and cell assay demonstrate that SAPs possess two integrated functions of (i) amyloid inhibition for preventing both Aβ and hIAPP aggregation by 34–61% and reducing their induced cytotoxicity by 7.6–35.4% and (ii) amyloid sensing for early detection of toxic Aβ and hIAPP aggregates using in-house SAP-based paper sensors and SPR sensors. The presence of both amyloid inhibition and detection in SAPs stems from strong molecular interactions between amyloid aggregates and SAPs, thus providing a new multi-target model for expanding the new therapeutic potentials of SAPs and other designs with built-in amyloid inhibition and detection functions. 

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