Early Cellular, Molecular, Morphological and Behavioral Changes in the Humanized Amyloid-Beta-Knock-In Mouse Model of Late-Onset Alzheimer's Disease.

The purpose of our study is to investigate early cellular, molecular, morphological and behavioral changes in humanized amyloid-beta-knock-in (hAbKI) mice. Using seven-month-old homozygous hAbKI mice, we studied behavioral phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity (open field), working memory (Y-maze) and motor coordination (rotarod); mRNA abundance, protein levels, soluble amyloid-beta 40 and 42 levels and regional immunoreactivities of key markers of mitochondrial dynamics, mitochondrial biogenesis, synaptic health, mitophagy and autophagy; mitochondrial function and using transmission electron microscopy & Golgi-Cox staining, we assessed mitochondrial morphology and dendritic spines. Our extensive behavioral analysis revealed that seven-month-old hAbKI mice showed impairments in motor coordination, reduced locomotor and exploration activities, impairments in working memory and spatial learning and memory. Our mRNA and protein analyses revealed the increased expression of mitochondrial-fission genes and reduced expression of mitochondrial-fusion, mitochondrial-biogenesis, synaptic, autophagy and mitophagy genes in seven-month-old hAbKI mice. An immunofluorescence analysis revealed altered immunoreactivities and agreed with the immunoblot results. Transmission-electron-microscopy data revealed increased mitochondrial fragmentation and reduced mitochondrial length in both hippocampal and cortical tissues of seven-month-old hAbKI mice and mitochondrial function defective. A Golgi-Cox-staining analysis revealed reduced dendritic spines in both cerebral cortices and hippocampi of hAbKI mice. Soluble amyloid-beta (1-40 and 1-42) were detected in three-month-old hAbKI mice and progressively increased in seven-month-old mice. These observations suggest that the human amyloid-beta peptide is sufficient to cause behavioral, mitochondrial, synaptic and ultrastructural changes in seven-month-old hAbKI mice. Our study findings also suggest that hAbKI mice might serve as a model for preclinical studies of preventive therapies.

Protective Effects of Chaya against Mitochondrial and Synaptic Toxicities in the Type 2 Diabetes Mouse Model TallyHO.

The purpose of our study is to determine the protective effects of the chaya leaf against mitochondrial abnormalities and synaptic damage in the Type 2 diabetes (T2D) mouse model, TallyHO (TH). The TH mouse is a naturally occurring polygenic mouse model of diabetes that mimics many characteristics of human Type 2 diabetes. Only male TH mice develop hyperglycemia and moderate obesity. Female mice display moderate obesity but do not manifest overt diabetes. In this study, we evaluated three groups of mice over a period of 11 weeks: (1) the experimental group of TH diabetic mice fed with chaya chow; (2) a diabetic control group of TH diabetic mice fed with regular chow; and (3) a non-diabetic control group of SWR/J mice fed with regular chow. Body mass and fasting blood glucose were assessed weekly. Brain and other peripheral tissues were collected. Using qRT-PCR and immunoblotting analyses, we measured the mRNA abundance and protein levels of mitochondrial biogenesis, mitochondrial dynamics, autophagy/mitophagy, and synaptic genes. Using immunofluorescence analysis, we measured the regional immunoreactivities of mitochondrial and synaptic proteins. Using biochemical methods, we assessed mitochondrial function. We found increased body mass and fasting glucose levels in the TH diabetic mice relative to the non-diabetic control SWRJ mice. In chaya chow-fed TH diabetic mice, we found significantly reduced body mass and fasting glucose levels. Mitochondrial fission genes were increased and fusion, biogenesis, autophagy/mitophagy, and synaptic genes were reduced in the TH mice; however, in the chaya chow-fed TH diabetic mice, mitochondrial fission genes were reduced and fusion, biogenesis, autophagy/mitophagy, and synaptic genes were increased. Mitochondrial function was defective in the diabetic TH mice; however, it was rescued in the chaya chow-fed TH mice. These observations strongly suggest that chaya chow reduces the diabetic properties, mitochondrial abnormalities, and synaptic pathology in diabetic, TH male mice. Our data strongly indicates that chaya can be used as natural supplemental diet for prediabetic and diabetic subjects and individuals with metabolic disorders.

Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. AD is marked by multiple cellular changes, including deregulation of microRNAs, activation of glia and astrocytes, hormonal imbalance, defective mitophagy, synaptic degeneration, in addition to extracellular neuritic amyloid-beta (Aß) plaques, phosphorylated tau (P-tau), and intracellular neurofibrillary tangles (NFTs). Recent research in AD revealed that defective synaptic mitophagy leads to synaptic degeneration and cognitive dysfunction in AD neurons. Our critical analyses of mitochondria and Aß and P-tau revealed that increased levels of Aß and P-Tau, and abnormal interactions between Aß and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and proliferation of dysfunctional mitochondria in AD neurons and depleted Parkin and PINK1 levels. These events ultimately lead to impaired clearance of dead and/or dying mitochondria in AD neurons. The purpose of our article is to highlight the recent research on mitochondria and synapses in relation to Aß and P-tau, focusing on recent developments.

Protective effects of a mitochondria-targeted small peptide SS31 against hyperglycemia-induced mitochondrial abnormalities in the liver tissues of diabetic mice, Tallyho/JngJ mice.

Type 2 Diabetes mellitus (T2DM) has become a major public health issue associated with a high risk of late-onset Alzheimer's disease (LOAD). Mitochondrial dysfunction is one of the molecular events that occur in the LOAD pathophysiology. The present study was planned to investigate the molecular alterations induced by hyperglycemia in the mitochondria of diabetic mice and further explore the possible ameliorative role of the mitochondria-targeted small peptide, SS31 in diabetic mice. For this purpose, we used a polygenic mouse model of type 2 diabetes, TALLYHO/JngJ (TH), and nondiabetic, SWR/J mice strains. The diabetic status in TH mice was confirmed at 8 weeks of age. The 24 weeks old experimental animals were segregated into three groups: Non-diabetic controls (SWR/J mice), diabetic (TH mice) and, SS31 treated diabetic TH mice. The mRNA and protein expression levels of mitochondrial proteins were investigated in all the study groups in the liver tissues using qPCR and immunoblot analysis. Also, the mitochondrial functions including H2O2 production, ATP generation, and lipid peroxidation were assessed in all the groups. Mitochondrial dysfunction was observed in TH mice as evident by significantly elevated H2O2 production, lipid peroxidation, and reduced ATP production. The mRNA expression and Western blot analysis of mitochondrial dynamics (Drp1 and Fis1 - fission; Mfn1, Mfn2, and Opa1 -fusion), and biogenesis (PGC-1α, Nrf1, Nrf2, and TFAM) genes were significantly altered in diabetic TH mice. Furthermore, SS31 treatment significantly reduced the mitochondrial abnormalities and restore mitochondrial functions in diabetic TH mice.

Are TallyHo Mice A True Mouse Model for Type 2 Diabetes and Alzheimer's Disease?

The purpose of our article is to critically assess if TallyHo mice are a true mouse model for type 2 diabetes and Alzheimer's disease. Diabetes is a lifestyle condition that is characterized by elevated blood glucose due to either insufficient amount of insulin or the body's inability to use the produced insulin efficiently. Diabetes occurs in multiple forms, including type 1, type 2, type 3, neonatal, and gestational. Type 2 diabetes covers 95% of overall diabetes, found in individuals 65 years of age and above. Both modifiable and non-modifiable factors are involved in developing diabetes. In patients with diabetes, increased blood glucose levels are reported to induce multiple complications, such as heart disease, stroke, kidney failure, foot ulcers, and damage to the eyes. However, the molecular basis of diabetes is not completely understood. Further, there are no accurate animal model(s) that mimic both type 1 and type 2 diabetes of humans. Multiple polygenic models are being used, including the Goto-Kakizaki rat, the Otzhka Long-Evans Tokushima Fatty rat, the Nagoya Shibata Yasuda mouse, the New Zealand obese mouse, the Tsumura-Suzuki obese diabetes mouse, leptin deficient ob/ob and the leptin receptor deficient db/db mouse models. In 2001, Kim and colleagues described the TallyHo mice that represent many features of type 2 diabetes of humans. Since then, several groups studied TallyHo mice. Only the male mice develop hyperglycemia and the females exhibit features of obesity. Thus, this model can be used to study both diabetes and obesity. The purpose of this article is to discuss recent developments in TallyHo mice research including diabetes onset and progression.

Current Status of Healthy Aging and Dementia Research: A Symposium Summary.

The purpose of the 'First Regional Healthy Aging and Dementia Research Symposium' was to discuss the latest research in healthy aging and dementia research, public health trends related to neurodegenerative diseases of aging, and community-based programs and research studying health, nutrition, and cognition. This symposium was organized by the Garrison Institute on Aging (GIA) of the Texas Tech University Health Sciences Center (TTUHSC), and was held in Lubbock, Texas, October 24-25, 2018. The Symposium joined experts from educational and research institutions across the United States. The two-day Symposium included all GIA staff and researchers. Students, postdoctoral fellows, and faculty members involved in dementia research presented at the Symposium. Healthcare professionals, from geriatricians to social workers working with patients with neurodegenerative diseases, also presented. In addition, experts traveled from across the United States to participate. This event was comprised of multiple sessions, each with several oral presentations, followed by questions and answers, and discussion.

Characterization of the Vibrio cholerae vceCAB multiple-drug resistance efflux operon in Escherichia coli.

Herein, we identify vceC as a component of a vceCAB operon, which codes for the Vibrio cholerae VceAB multiple-drug resistance (MDR) efflux pump, and vceR, which codes for a transcriptional autoregulatory protein that negatively regulates the expression of the vceCAB operon and is modulated by some of the substrates of this MDR efflux pump.