Dynamics of Dynamin-Related Protein 1 in Alzheimer's Disease and Other Neurodegenerative Diseases.

The purpose of this article is to highlight the role of dynamin-related protein 1 (Drp1) in abnormal mitochondrial dynamics, mitochondrial fragmentation, autophagy/mitophagy, and neuronal damage in Alzheimer's disease (AD) and other neurological diseases, including Parkinson's, Huntington's, amyotrophic lateral sclerosis, multiple sclerosis, diabetes, and obesity. Dynamin-related protein 1 is one of the evolutionarily highly conserved large family of GTPase proteins. Drp1 is critical for mitochondrial division, size, shape, and distribution throughout the neuron, from cell body to axons, dendrites, and nerve terminals. Several decades of intense research from several groups revealed that Drp1 is enriched at neuronal terminals and involved in synapse formation and synaptic sprouting. Different phosphorylated forms of Drp1 acts as both increased fragmentation and/or increased fusion of mitochondria. Increased levels of Drp1 were found in diseased states and caused excessive fragmentation of mitochondria, leading to mitochondrial dysfunction and neuronal damage. In the last two decades, several Drp1 inhibitors have been developed, including Mdivi-1, Dynasore, P110, and DDQ and their beneficial effects tested using cell cultures and mouse models of neurodegenerative diseases. Recent research using genetic crossing studies revealed that a partial reduction of Drp1 is protective against mutant protein(s)-induced mitochondrial and synaptic toxicities. Based on findings from cell cultures, mouse models and postmortem brains of AD and other neurodegenerative disease, we cautiously conclude that reduced Drp1 is a promising therapeutic target for AD and other neurological diseases.

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.

Amyloid Beta and Phosphorylated Tau-Induced Defective Autophagy and Mitophagy in Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Several decades of intense research have revealed that multiple cellular changes are implicated in the development and progression of AD, including mitochondrial damage, synaptic dysfunction, amyloid beta (Aß) formation and accumulation, hyperphosphorylated tau (P-Tau) formation and accumulation, deregulated microRNAs, synaptic damage, and neuronal loss in patients with AD. Among these, mitochondrial dysfunction and synaptic damage are early events in the disease process. Recent research also revealed that Aß and P-Tau-induced defective autophagy and mitophagy are prominent events in AD pathogenesis. Age-dependent increased levels of Aß and P-Tau reduced levels of several autophagy and mitophagy proteins. In addition, abnormal interactions between (1) Aß and mitochondrial fission protein Drp1; (2) P-Tau and Drp1; and (3) Aß and PINK1/parkin lead to an inability to clear damaged mitochondria and other cellular debris from neurons. These events occur selectively in affected AD neurons. The purpose of our article is to highlight recent developments of a Aß and P-Tau-induced defective autophagy and mitophagy in AD. This article also summarizes several aspects of mitochondrial dysfunction, including abnormal mitochondrial dynamics (increased fission and reduced fusion), defective mitochondrial biogenesis, reduced ATP, increased free radicals and lipid peroxidation, and decreased cytochrome c oxidase (COX) activity and calcium dyshomeostasis in AD pathogenesis. Our article also discusses how reduced levels of Drp1, Aß, and P-Tau can enhance the clearance of damaged mitochondria and other cellular debris by autophagy and mitophagy mechanisms.

Molecular Basis of Alzheimer's Disease: Focus on Mitochondria.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. With the increased aging population, AD is a major health concern in society. Morphological and pathological studies revealed that AD is associated with the loss of synapses, defective mitochondria, and the proliferation of reactive astrocytes and microglia, in addition to the presence amyloid-ß and phosphorylated tau in learning and memory regions of the brain in AD patients. AD occurs in two forms: early-onset familial and late-onset sporadic. Genetic mutations in APP, PS1, and PS2 loci cause familial AD. Multiple factors are reported to be involved in late-onset AD, including APOE4 genotype, polymorphisms in several gene loci and type 2 diabetes, traumatic brain injury, stroke, and age-related factors, including increased reactive oxygen species production and dysfunction in mitochondria. It is widely accepted that synaptic damage and mitochondrial dysfunction are early events in disease process. The purpose of this article is to highlight molecular triggers to the disease process. This article also reviews factors, including age, gender, lifestyle, epigenetic factors, and type 2 diabetes, that are involved in late-onset AD. This article also discusses recent developments in research of mitochondrial structure, function, physiology, dynamics, biogenesis, mitophagy, and mitochondrial DNA changes in healthy and diseased states.

Small molecules as therapeutic drugs for Alzheimer's disease.

Mitochondrial dysfunction is a central protagonist of Alzheimer's disease (AD) pathogenesis. Mitochondrial dysfunction stems from various factors including mitochondrial DNA damage and oxidative stress from reactive oxygen species, membrane and ionic gradient destabilization, and interaction with toxic proteins such as amyloid beta (Aß). Therapeutic drugs such as cholinesterase and glutamate inhibitors have proven to improve synaptic neurotransmitters, but do not address mitochondrial dysfunction. Researchers have demonstrated that oxidative damage may be reduced by increasing endogenous antioxidants, and/or increasing exogenous antioxidants such as vitamin C & E, beta-carotene and glutathione. Nonetheless, as AD pathology intensifies, endogenous antioxidants are overwhelmed, and exogenous antioxidants are unable to reach neuronal mitochondria as they are blocked by the blood brain barrier. Current therapeutic methods however include novel usage of lipophilic phosphonium cation bound to antioxidants, to effect neuronal mitochondria targeted activity. Mitochondria targeted MitoQ, MitoVitE, MitoTempo, MitoPBN and MCAT concentrate within mitochondria where they scavenge free-radicals, and augment mitochondrial dysfunction. Additional molecules include Szeto-Schiller (SS) peptides which target stability of the inner mitochondrial membrane, and DDQ molecule capable of improving bioenergetics and reduce mitochondrial fragmentation. This article discusses advantages and disadvantages of small molecules, their ability to mitigate Aß induced damage, and ability to ameliorate synaptic dysfunction and cognitive loss.

Qualitative and quantitative drug residue analyses: Chlortetracycline in white-tailed deer (Odocoileus virginianus) and supermarket meat by liquid chromatography tandem-mass spectrometry.

Chlortetracycline is (CTC) is a tetracycline antibiotic which is being in the white-tailed deer industry to improve production and animal health. In this paper, we present a method for determining chlortetracycline residues in edible white-tailed deer tissues, using liquid chromatography with heated electrospray ionization and mass spectrometry detection. The procedure involved extraction with EDTA-McIlvaine buffer at pH 4.0, followed by solid-phase extraction cleanup using a hydrophilic-lipophilic balance (HLB) cartridge. The liquid chromatography analysis was performed with heated electrospray ionization and mass spectrometry detection. The limit of quantification for the method was 2.7 ng/g and limit of detection was 0.8 ng/g. The recovery values were >78.5% for muscle, 65.1% for kidney, 63.1% for liver. Mean tissue residue concentration of chlortetracycline and it's epimer, 4-epi chlortetracycline (4-epi-CTC) at 10-day withdrawal period for kidney, liver, muscle was 122.8, 44.7 and 26.7 ng/g, respectively. Chlortetracycline tissue residue concentration at 45-day withdrawal period for kidney, liver, muscle was 19.2, 28.9 and 10.7 ng/g, respectively. Mean tissue concentration of CTC was less than the established maximum residual limit (MRL) values for bovine tissues. We have validated and successfully applied this method in the qualitative and quantification of chlortetracycline in white-tailed deer tissue samples.