Volume 72, Supplement 1, 2019

Pages S1-S10
Introductory Review

P. Hemachandra Reddy
Lifestyle and Risk Factors of Dementia in Rural West Texas
Abstract: In October 2018, the Texas Tech University Health Sciences Center (TTUHSC) held its first annual Healthy Aging and Dementia Research Symposium. The symposium was conceived and organized by the TTUHSC Garrison Institute on Aging. Its overall objective was to bring together scientists, healthcare professionals, interns, graduate students, postdoctoral fellows, faculty members, and NIH officials in order to share research results on aging and dementia associated with Alzheimer’s disease and to discuss possible lines of research that may be productive in reducing dementia associated with Alzheimer’s disease and, ultimately, associated with other neurological diseases. Another objective of the symposium was to share information, through formal and informal presentations, on whether and how unmodifiable factors, such as aging, and modifiable lifestyle factors, such diet and physical activity, impact dementia specifically and other chronic and neurological diseases, including diabetes and Alzheimer’s disease. Discussions of the relationship across aging, dementia, and chronic and neurological diseases, and of the impact of lifestyles on these diseases mainly focused on populations living in the rural areas of West Texas counties since these areas are known to have populations of extremely different lifestyles. This introduction gives background on research of dementia associated with Alzheimer’s disease, on populations and lifestyles of persons in rural West Texas, and on lifestyle factors known to affect progression of dementia and neurological diseases.

Pages S11-S35

P. Hemachandra Reddy, Russell H. Swerdlow, John Culberson, David Kang, Tedd L. Mitchell, Quentin Smith, Sanoj Suneja, Marcia G. Ory, Subodh Kumar, Murali Vijayan, Ahmed Morsy, Gabriela Arandia, J. Josh Lawrence, Elizabeth George, Darryll Oliver, Jangampalli Adi Pradeepkiran, Xiangling Yin, Arubala P. Reddy, Maria Manczak, Pelin Cengiz, Vardan T. Karamyan, Ramesh Kandimalla, Chandra Sekhar Kuruva, Joshua Willms, Bhagavathi Ramasubramanian, Neha Sawant, Divya Burugu, Annette N. Boles, Veronica Lopez, Rocio Carrasco, Cordelia Aguirre, Susan Thompson, Joan Blackmon, Clay Ament, Rui Wang, Emily R. Stephens, Brittney Hoang, Kevin Bass, Paul C. Trippier, Christopher Hornback, Pratibha Kottapalli, Kameswara Rao Kottapalli, Center Biotechnology and Genetics Core Facility, Salvatore Oddo
Current Status of Healthy Aging and Dementia Research: A Symposium Summary
Abstract: 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.

Pages S37-S58

Elizabeth Kurudamannil George, P. Hemachandra Reddy
Can Healthy Diets, Regular Exercise, and Better Lifestyle Delay the Progression of Dementia in Elderly Individuals?
Abstract: Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. Current healthcare costs for over 50 million people afflicted with AD are about $818 million and are projected to be $2 billion by 2050. Unfortunately, there are no drugs currently available that can delay and/or prevent the progression of disease in elderly individuals and in AD patients. Loss of synapses and synaptic damage are largely correlated with cognitive decline in AD patients. Women are at a higher lifetime risk of developing AD encompassing two-thirds of the total AD afflicted population. Only about 1-2% of total AD patients can be explained by genetic mutations in APP, PS1, and PS2 genes. Several risk factors have been identified, such as Apolipoprotein E4 genotype, type 2 diabetes, traumatic brain injury, depression, and hormonal imbalance, are reported to be associated with late-onset AD. Strong evidence reveals that antioxidant enriched diets and regular exercise reduces toxic radicals, enhances mitochondrial function and synaptic activity, and improves cognitive function in elderly populations. Current available data on the use of antioxidants in mouse models of AD and antioxidant(s) supplements in diets of elderly individuals were investigated. The use of antioxidants in randomized clinical trials in AD patients was also critically assessed. Based on our survey of current literature and findings, we cautiously conclude that healthy diets, regular exercise, and improved lifestyle can delay dementia progression and reduce the risk of AD in elderly individuals and reverse subjects with mild cognitive impairment to a non-demented state.

Pages S59-S69
Hafiz Khan, Aamrin Rafiq, Obadeh Shabaneh, LisaAnn S. Gittner, P. Hemachandra Reddy
Current Issues in Chronic Diseases: A Focus on Dementia and Hypertension in Rural West Texans
Abstract: Dementia and hypertension are chronic diseases that affect elderly populations worldwide. The prevalence of these diseases increases each year, especially in rural and underserved rural communities like West Texas. The purpose of this study was to find risk factors of dementia and their impact on West Texans. Data was provided by the Project FRONTIER for rural West Texas counties. The SPSS software package was used for statistical analysis. Pearson’s chi-squared test was also utilized to determine relationships between the risk factors considering a level of significance (α) = 0.05. The findings have shown that age group had significant associations with hypertension, cerebral, neurologic disease, Romberg test, and muscle strength for both males and females (p≤0.002). Hypertension was significantly associated with cognitive disorder and diabetes in both males and females (p≤0.011). Age group in females was significantly associated with parkinsonism (p=0.02), neurological stroke (p=0.002), reflexes (p=0.003), and sensory intact (hands/feet) (p=0.004), respectively, whereas age for males was not significantly associated with those variables (p=0.29, p=0.05, p=0.56, and p=0.76, respectively). Hypertension in females was significantly associated with cardiovascular disease (p=0.001) and depression (p=0.001) but was not found to be significant for males (p=0.30 and p=0.09, respectively). Both males and females in Hispanic and non-Hispanic groups were found to be significantly associated with Alzheimer’s disease (p=0.0001 and p=0.045, respectively). Hispanic and non-Hispanic females were found to be significantly associated with hypertension (p=0.026). Gender-specific differences in dementia risk factors exist and integrating such variables may guide relevant policymaking to reduce dementia incidence in rural West Texas.

Pages S71-S79

Vijay Hegde, Nikhil V. Dhurandhar, P. Hemachandra Reddy
Hyperinsulinemia or Insulin Resistance: What Impacts the Progression of Alzheimer’s Disease?
Abstract: Type 2 diabetes mellitus (T2D), which is often accompanied by hyperinsulinemia and insulin resistance, is associated with an increased risk for developing mild cognitive impairment and Alzheimer’s disease (AD); however, the underlying mechanisms for this association are still unclear. Recent findings have shown that hyperinsulinemia and insulin resistance can coexist or be independent events. This makes it imperative to determine the contribution of these individual conditions in impacting AD. This literature review highlights the recent developments of hyperinsulinemia and insulin resistance involvement in the progression and pathogenesis of AD.

Pages S81-S93

Bhagavathi Ramasubramanian, P. Hemachandra Reddy
Are TallyHo Mice A True Mouse Model for Type 2 Diabetes and Alzheimer’s Disease?
Abstract: 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.

Pages S95-S116

Darryll M.A. Oliver, P. Hemachandra Reddy
Molecular Basis of Alzheimer’s Disease: Focus on Mitochondria
Abstract: 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-β 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.

Pages S117-S130

Subodh Kumar, P. Hemachandra Reddy
A New Discovery of MicroRNA-455-3p in Alzheimer’s Disease
Abstract: MicroRNA-455-3p (miR-455-3p) is identify as a member of broadly conserved miRNA family expressed in most of the phylum and species. In humans, miR-455 is present on the human chromosome 9 at locus 9q32 and encoded by the human COL27A1 gene (collagen type XXVII alpha 1 chain). The role of miR-455 has been implicated in various human diseases such as cartilage development, adipogenesis, preeclampsia, and cancers, e.g., colon cancer, prostate cancer, hepatocellular carcinoma, renal cancer, oral squamous cancer, skin cancer, and non-small cell lung cancer. Recently, our laboratory discovered the biomarker and therapeutic relevance of miR-455-3p in Alzheimer’s disease (AD). Our global microarray analysis of serum samples from AD patients, mild cognitive individuals (MCI), and healthy subjects unveiled the high level of miR-455-3p in AD patients relative to MCI and healthy controls. Further, validation analysis using different kinds of AD samples such as serum, postmortem brains, AD fibroblasts, AD B-lymphocytes, AD cell lines, AD mouse models, and AD cerebrospinal fluid confirmed the biomarker potential of miR-455-3p. The mechanistic link of miR-455-3p in AD was determined via modulation of amyloid-β protein precursor (AβPP) and amyloid-β (Aβ) levels. Luciferase reporter assay confirmed AβPP as validated target of miR-455-3p. Our study on mouse neuroblastoma cells revealed the protective role of miR-455-3p against Aβ-induced toxicities. We also noticed that miR-455-3p enhances cell survival and lifespan extension. High level of miR-455-3p reduces Aβ toxicity, enhances mitochondrial biogenesis and synaptic activity, and maintains healthy mitochondrial dynamics. Based on these evidences, we cautiously conclude that miR-455-3p is a promising peripheral biomarker and therapeutic candidate for AD.

Pages S131-S144

David E. Kang, Jung A. Woo
Cofilin, a Master Node Regulating Cytoskeletal Pathogenesis in Alzheimer’s Disease
Abstract: The defining pathological hallmarks of Alzheimer’s disease (AD) are proteinopathies marked by the amyloid-β (Aβ) peptide and hyperphosphorylated tau. In addition, Hirano bodies and cofilin-actin rods are extensively found in AD brains, both of which are associated with the actin cytoskeleton. The actin-binding protein cofilin known for its actin filament severing, depolymerizing, nucleating, and bundling activities has emerged as a significant player in AD pathogenesis. In this review, we discuss the regulation of cofilin by multiple signaling events impinging on LIM kinase-1 (LIMK1) and/or Slingshot homolog-1 (SSH1) downstream of Aβ. Such pathophysiological signaling pathways impact actin dynamics to regulate synaptic integrity, mitochondrial translocation of cofilin to promote neurotoxicity, and formation of cofilin-actin pathology. Other intracellular signaling proteins, such as β-arrestin, RanBP9, Chronophin, PLD1, and 14-3-3 also impinge on the regulation of cofilin downstream of Aβ. Finally, we discuss the role of activated cofilin as a bridge between actin and microtubule dynamics by displacing tau from microtubules, thereby destabilizing tau-induced microtubule assembly, missorting tau, and promoting tauopathy.

Pages S145-S176

Ahmed Morsy, Paul C. Trippier
Current and Emerging Pharmacological Targets for the Treatment of Alzheimer’s Disease
Abstract: No cure or disease-modifying therapy for Alzheimer’s disease (AD) has yet been realized. However, a multitude of pharmacological targets have been identified for possible engagement to enable drug discovery efforts for AD. Herein, we review these targets comprised around three main therapeutic strategies. First is an approach that targets the main pathological hallmarks of AD: amyloid-β (Aβ) oligomers and hyperphosphorylated tau tangles which primarily focuses on reducing formation and aggregation, and/or inducing their clearance. Second is a strategy that modulates neurotransmitter signaling. Comprising this strategy are the cholinesterase inhibitors and N-methyl-D-aspartate receptor blockade treatments that are clinically approved for the symptomatic treatment of AD. Additional targets that aim to stabilize neuron signaling through modulation of neurotransmitters and their receptors are also discussed. Finally, the third approach comprises a collection of ‘sensitive targets’ that indirectly influence Aβ or tau accumulation. These targets are proteins that upon Aβ accumulation in the brain or direct Aβ-target interaction, a modification in the target’s function is induced. The process occurs early in disease progression, ultimately causing neuronal dysfunction. This strategy aims to restore normal target function to alleviate Aβ-induced toxicity in neurons. Overall, we generally limit our analysis to targets that have emerged in the last decade and targets that have been validated using small molecules in in vitro and/or in vivo models. This review is not an exhaustive list of all possible targets for AD but serves to highlight the most promising and critical targets suitable for small molecule drug intervention.

Pages S177-S191

Neha Sawant, P. Hemachandra Reddy
Role of Phosphorylated Tau and Glucose Synthase Kinase 3 Beta in Huntington’s Disease Progression
Abstract: The purpose of our article is to critically assess the role of phosphorylated tau in Huntington’s disease (HD) progression and pathogenesis. HD is a fatal and pure genetic disease, characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. HD is caused by expanded polyglutamine (polyQ or CAG) repeats within the exon 1 of the HD gene. HD has an autosomal dominant pattern of inheritance with genetic anticipation. Although the HD gene was discovered 16 years ago, there is no complete understanding of how mutant huntingtin (mHTT) selectively targets medium spiny projection neurons in the basal ganglia of the brain in patients with HD. Several years of intense research revealed that multiple cellular changes are involved in disease process, including transcriptional dysregulation, mitochondrial abnormalities and impaired bioenergetics, defective axonal transport, calcium dyshomeostasis, synaptic damage and caspase, and NMDAR activations. Recent research also revealed that phosphorylated tau and defective GSK-3β signaling are strongly linked to progression of the disease. This article summarizes the recent developments of cellular and pathological changes in disease progression of HD. This article also highlights recent developments in phosphorylated tau and defective GSK-3β signaling and the involvement of calcineurin in HD progression and pathogenesis.