TDP-43 Proteinopathy in Aging: Associations with Risk-Associated Gene Variants and with Brain Parenchymal Thyroid Hormone Levels

TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer\u27s disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer\u27s Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy

Investigating the Effects of Homocysteine as an Agonist on Invertebrate Glutamatergic Synapses

Hyperhomocysteinemia (HHcy) in mammals can produce neurological deficits, such as memory loss. The cause of the neurological issues is assumed to be due to homocysteine (HCY) binding to glutamatergic receptors in the central nervous system (CNS). High levels of HCY in the CNS are also associated with Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease. Thus, understanding the detailed mechanisms of HCY in model preparations could be useful in developing potential treatments to neurodegenerative diseases with overlapping symptoms to HHcy. The aim of this study is to investigate the efficacy of HCY as an agonist at glutamatergic synapses in invertebrates. The glutamatergic synapses of the larval Drosophila melanogaster (D. melanogaster) and Procambarus clarkii (P. clarkii) neuromuscular junctions (NMJs) were utilized to examine the effects of applying HCY. Measurements of evoked synaptic transmission in both preparations revealed that 100 mM of HCY did not have any consistent effect. The expectation was that the acute action of HCY would have activated the glutamate receptors and then desensitized them so evoked transmission would be blocked. The pharmacological receptor profile of these NMJ receptors are of a quisqualate subtype and not a kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate receptor (NMDA) subtype. Consequently, HCY may not have any action on quisqualate glutamate receptor subtypes. The findings of this experiments could provide clinical implications regarding relevant pharmacological treatments in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease

Effects of Clove Oil (Eugenol) on Proprioceptive Neurons, Heart Rate, and Behavior in Model Crustaceans

Clove oil contains eugenol as an active ingredient and is used as a topical anesthetic in mammals to remedy pain and to anesthetize fish and other seafood for short periods; however, the exact mechanism of action of eugenol is not fully understood. We examined use of eugenol as a reversible anesthetic in crustaceans by examining its effect on sensory and motor neurons in the Red Swamp crayfish (Procambarus clarkii), Blue crab (Callinectes sapidus) and Whiteleg shrimp (Litopenaeus vannamei) with electrophysiological recordings. The neurogenic heart rate in the three species was also monitored along with behaviors and responsiveness to sensory stimuli. The activity of the primary proprioceptive neurons was reduced at 200 ppm and ceased at 400 ppm for both crayfish (i.e., muscle receptor organ) and crab (i.e., leg PD organ) preparations when exposed to saline containing eugenol. Flushing out eugenol resulted in recovery in the majority of the preparations within five to ten minutes. Administering eugenol to crayfish and crabs both systemically and through environmental exposure resulted in the animals becoming lethargic. Direct injection into the hemolymph was quicker to decrease reflexes and sensory perception, but heart rate was still maintained. Eugenol at a circulating level of 400 ppm decreased electromyogram activity in the claw muscle of crabs. Surprisingly, this study found no change in heart rate despite administering eugenol into the hemolymph to reach 400 ppm in crabs or crayfish but heart rate in shrimp preparations decreased. Our results demonstrate the feasibility of eugenol as a short-term anesthetic for crustaceans to decrease stress during handling or transportation, considering its effectiveness at decreasing sensory input and the quick recovery of upon removal of eugenol. A neurophysiology course took this project on as an authentic course-based undergraduate research experience (ACURE)

Von der Ethnogenese zur Identitätsforschung

Hyperhomocysteinemia (HHcy) in mammals can produce neurological deficits, such as memory loss. The cause of the neurological issues is assumed to be due to homocysteine (HCY) binding to glutamatergic receptors in the central nervous system (CNS). High levels of HCY in the CNS are also associated with Amyotrophic Lateral Sclerosis (ALS) and Parkinson’s disease. Thus, understanding the detailed mechanisms of HCY in model preparations could be useful in developing potential treatments to neurodegenerative diseases with overlapping symptoms to HHcy. The aim of this study is to investigate the efficacy of HCY as an agonist at glutamatergic synapses in invertebrates. The glutamatergic synapses of the larval Drosophila melanogaster (D. melanogaster) and Procambarus clarkii (P. clarkii) neuromuscular junctions (NMJs) were utilized to examine the effects of applying HCY. Measurements of evoked synaptic transmission in both preparations revealed that 100 mM of HCY did not have any consistent effect. The expectation was that the acute action of HCY would have activated the glutamate receptors and then desensitized them so evoked transmission would be blocked. The pharmacological receptor profile of these NMJ receptors are of a quisqualate subtype and not a kainate, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate receptor (NMDA) subtype. Consequently, HCY may not have any action on quisqualate glutamate receptor subtypes. The findings of this experiments could provide clinical implications regarding relevant pharmacological treatments in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease