Biology subjects

Terry, A. V.

Publications and source records attributed to Terry, A. V..

4 recordsLinked to original sources

bioRxiv2025

GM1 and GD3 Gangliosides Attenuate NGF-TrkA and BDNF-TrkB Signaling Dysfunction Associated with Acute Diisopropylfluorophosphate Exposure in Mouse Brain

The prevalence of neurodegenerative diseases and mental health disorders has been increasing over the past few decades. While genetic and lifestyle factors are important to the etiology of these illnesses, the pathogenic role of environmental factors, especially toxicants such as pesticides encountered over the life span, is receiving increased attention. As an environmental factor, organophosphates pose a constant threat to human health due to their widespread use as pesticides, their deployment by rogue militaries, and their use in terrorist attacks. The standard organophosphate-antidotal regimen provides modest efficacy against lethality, although morbidity remains high, and there is little evidence that it attenuates long-term neurobehavioral sequelae. Here we show that a novel intranasally administered treatment strategy with specific gangliosides can prevent the organophosphate-related alterations in important neurotrophin pathways that are involved in cognition and depression. We found that a single toxic dose of the organophosphate diisopropylfluorophosphate (DFP) in mice leads to persistent decreases in the neurotrophins NGF and BDNF and their receptors, TrkA and TrkB. Moreover, seven days of repeated intranasal administration of gangliosides GM1 or GD3 24 hours after the DFP injection prevented the neurotrophin receptor alterations. As NGF and BDNF signaling are involved in cognitive function and depression symptoms, respectively, intranasal administration of GM1 or GD3 can prevent the organophosphate-related alterations in those brain functions. Our study thus supports the potential of a novel therapeutic strategy for neurological deficits associated with a class of poisons that endangers millions of people worldwide. Highlights O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/646417v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@edf17dorg.highwire.dtl.DTLVardef@1895982org.highwire.dtl.DTLVardef@538e99org.highwire.dtl.DTLVardef@1b700d3_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LIA single exposure to DFP, which causes cognitive deficits, dysregulates NGF and BDNF signaling C_LIO_LIGM1 or GD3 24 hours after DFP injection prevents the alteration of the neurotrophin signaling C_LIO_LIIntranasal ganglioside treatment provides neuroprotective effects against persistent organophosphate toxicity C_LI

pharmacology and toxicology↗

bioRxiv2024

Intermittent stimulation of the basal forebrain improves working memory in aged nonhuman primates.

Brain aging contributes to cognitive decline and risk of dementia. Degeneration of the basal forebrain cholinergic system parallels these changes in aging, Alzheimers dementia, Parkinsons dementia, and Lewy body dementia, and thus is a common element linked to executive function across the lifespan and in disease states. Here, we tested the potential of one-hour daily intermittent basal forebrain stimulation to improve cognition in senescent monkeys, and its mechanisms of action. Stimulation in five animals improved working memory duration in 8-12 weeks across all animals, with peak improvements observed in the first four weeks. In an ensuing three month period without stimulation, improvements were retained. With additional stimulation, performance remained above baseline throughout the 15 months of the study. Studies with a cholinesterase inhibitor produced inconsistent improvements in behavior. One of five animals improved significantly. Manipulating the stimulation pattern demonstrated selectivity for both stimulation and recovery period duration. Brain stimulation led to acute increases in cerebrospinal levels of tissue plasminogen activator, which is an activating element for two brain neurotrophins, Nerve Growth Factor (NGF) and Brain-Derived Growth Factor (BDNF). Stimulation also led to improved glucose utilization in stimulated hemispheres relative to contralateral. Glucose utilization also consistently declines with aging and some dementias. Together, these findings suggest that intermittent stimulation of the nucleus basalis of Meynert improves executive function and reverses some aspects of brain aging. HighlightsO_LIThe basal forebrain and its cholinergic projections are the sole source of acetylcholine for the cortical mantle in primates and humans. C_LIO_LIForebrain function tracks cognitive loss throughout the adult lifespan. C_LIO_LIOne hour per day intermittent stimulation of this region improves executive function behaviors and plausibly reverses some aspects of brain aging, a large risk factor in dementias. C_LIO_LIThis stimulation exceeds impacts of standard pharmacotherapies, is enduring, recruits brain neurotrophic pathways and improves cortical glucose utilization. C_LI

neuroscience↗

bioRxiv2024

α7 nicotinic acetylcholine receptors are necessary for basal forebrain activation to increase expression of the nerve growth factor receptor TrkA

Activation of the basal forebrain leads to increases in the expression of the nerve growth factor receptor, Tropomyosin receptor kinase A (TrkA) and decreases in expression of the beta amyloid cleavage enzyme 1 (BACE1) in the cerebral cortex of both sexes of 5xFAD mice. The studies described in this report were designed to determine if these changes were dependent on acetylcholine receptors. Mice were stimulated unilaterally in the basal forebrain for two weeks. Animals were administered a cholinergic antagonist, or saline, 30 minutes prior to stimulation. Animals administered saline exhibited significant increases in TrkA expression and decreases in BACE1 in the stimulated hemisphere relative to the unstimulated. While both nonselective nicotinic and muscarinic acetylcholine receptor blockade attenuated the BACE1 decline, only the nicotinic receptor antagonism blocked the TrkA increase. Next, we applied selective nicotinic antagonists, and the 7 antagonist blocked the TrkA increases, but the 4{beta}2 antagonist did not. BACE1 declines were not blocked by either intervention. Mice with a loxP conditional knockout of the gene for the 7 nicotinic receptor were also employed in these studies. Animals were either stimulated bilaterally for two weeks, or left unstimulated. With or without stimulation, the expression of TrkA receptors was lower in the cortical region with the 7 nicotinic receptor knockdown. We thus conclude that 7 nicotinic receptor activation is necessary for normal expression of TrkA and increases caused by basal forebrain activation, while BACE1 declines caused by stimulation have dependency on a broader array of receptor subtypes.

neuroscience↗

bioRxiv2022

Cholinergic forebrain activation improves cognition, boosts neurotrophin receptors, and lowers Aβ42 levels in the cerebral cortex of 5xFAD mice.

The biological basis of Alzheimers dementia has been hypothesized in terms of basal forebrain cholinergic decline, and in terms reflecting the neuropathologies surrounding beta amyloid and tau. To shed light on the contributions of these different biological elements, we performed five month intermittent stimulation of the basal forebrain, which projects to the cortical mantle, in 5xFAD Alzheimers model mice and wild-type littermates, and subjected mice to behavioral testing and tissue analysis. The 5xFAD mice performed worse in water maze testing than their littermates. Stimulation improved both classes of mice, and removed performance differences between genotypes by the fifth testing day. Stimulated groups had two to four-fold increases in immunoblot measures of each of the neurotrophin receptors tropomyosin receptor kinase A and B. Stimulation also led to lower tissue A{beta}42 and beta amyloid cleavage enzyme 1 in 5xFAD mice. Despite the lack of strong direct projections from the basal forebrain stimulation region to the hippocampus, the hippocampal tissues in stimulated mice had more nerve growth factor receptor, and lower levels of beta secretase for amyloid. These data support a causal relation between forebrain cholinergic pathways and cognitive decline dependent on A{beta}42. Activation of cholinergic brain pathways improves neurotrophin pathways and reduces A{beta}42 accumulation. The recruitment of both classes of neurotrophin receptors in the process suggests a serine protease cleavage intermediary between cholinergic response and neurotrophin activation.

neuroscience↗