Developmental exposure to the Parkinson’s disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α- synuclein pre-formed fibril (PFF)-injected mice DOI Creative Commons
S. Boyd,

Nathan C. Kuhn,

Joseph R. Patterson

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: June 24, 2023

Abstract Parkinson’s disease (PD) is the most common movement disorder and one of fastest-growing neurological diseases worldwide. This increase outpaces rate aging rapid in recently industrialized areas, suggesting role environmental factors. Consistent with this, epidemiological studies show an association between exposure to persistent organic pollutants increased risk PD. When combined post-mortem analysis mechanistic studies, a for specific compounds, including organochlorine pesticide dieldrin, emerges. In mouse models, developmental dieldrin causes male-specific exacerbation neuronal susceptibility MPTP synucleinopathy. Specifically, our novel two-hit model combining α-synuclein (α-syn) pre-formed fibril (PFF) showed PFF-induced increases striatal dopamine (DA) turnover motor deficits on challenging beam 6 months post-PFF injection male offspring developmentally exposed dieldrin. Here, we hypothesized that alterations DA handling contribute observed changes assessed vesicular monoamine transporter 2 (VMAT2) function release this dieldrin/PFF model. Female C57BL/6 mice were 0.3 mg/kg or vehicle every 3 days, starting at 8 weeks age by feeding continuing throughout breeding, gestation, lactation. Male from independent litters underwent unilateral, intrastriatal injections α-syn PFFs via stereotaxic surgery 12 was 4 H-DA uptake assay fast-scan cyclic voltammetry (FSCV). We no dieldrin-associated change VMAT2 activity, but dieldrin-induced slices PFF-injected animals. These results suggest alters dopaminergic response synucleinopathy-triggered toxicity supports hypothesis may underly behavior turnover. Graphical

Language: Английский

Human tau-overexpressing mice recapitulate brainstem involvement and neuropsychiatric features of early Alzheimer’s disease DOI Creative Commons
Kanza M. Khan, Nagalakshmi Balasubramanian,

Gabriel Gaudencio

et al.

Acta Neuropathologica Communications, Journal Year: 2023, Volume and Issue: 11(1)

Published: April 3, 2023

Abstract Alzheimer’s disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in prodromal stages that may be partly driven by loss of monoaminergic neurons brainstem, but a causal relationship has not been firmly established. This is due part to dearth animal models recapitulate early neuropathology symptoms. The goal study was evaluate depressive anxiety-like behaviors mouse model overexpresses human wild-type tau (htau) prior onset cognitive impairments assess these behavior pathology, neuroinflammation, dysregulation dorsal raphe nucleus (DRN) locus coeruleus (LC). We observed depressive-like at 4 months both sexes hyperlocomotion male htau mice. Deficits social interaction persisted were accompanied increase males. behavioral coincided lower density serotonergic (5-HT) neurons, downregulation 5-HT markers, reduced excitability hyperphosphorylated DRN. Inflammatory markers also upregulated DRN along protein kinases transglutaminase 2, which promote phosphorylation aggregation. Loss innervation entorhinal cortex dentate gyrus hippocampus have contributed behaviors. There expression noradrenergic LC elevated phospho-tau expression, this did translate functional change neuronal excitability. In total, results suggest pathology brainstem nuclei resulting and/or drive underpin depressive- AD.

Language: Английский

Citations

23
Obesity during preclinical Alzheimer's disease development exacerbates brain metabolic decline DOI
Thea Anderson, Sumeet K. Sharma, Michael A. Kelberman

et al.

Journal of Neurochemistry, Journal Year: 2023, Volume and Issue: 168(5), P. 801 - 821

Published: June 30, 2023

Abstract Alzheimer's disease (AD) is the most common form of dementia. Obesity in middle age increases AD risk and severity, which alarming given that obesity prevalence peaks at rates are accelerating worldwide. Midlife, but not late‐life risk, suggesting this interaction specific to preclinical AD. pathology begins age, with accumulation amyloid beta (Aβ), hyperphosphorylated tau, metabolic decline, neuroinflammation occurring decades before cognitive symptoms appear. We used a transcriptomic discovery approach young adult (6.5 months old) male female TgF344‐AD rats overexpress mutant human precursor protein presenilin‐1 wild‐type (WT) controls determine whether inducing high‐fat/high‐sugar “Western” diet during brain dysfunction dorsal hippocampus (dHC), region vulnerable effects early Analyses dHC gene expression data showed dysregulated mitochondrial neurotransmission pathways, up‐regulated genes involved cholesterol synthesis. Western amplified number were different between WT added pathways noradrenergic signaling, inhibition synthesis, decreased intracellular lipid transporters. Importantly, impaired dHC‐dependent spatial working memory rats, confirming dietary intervention accelerated decline. To examine later consequences transcriptional dysregulation, we measured monoamine levels older (13 both sexes after long‐term chow or consumption. Norepinephrine (NE) abundance was significantly NE turnover increased, attenuated AD‐induced turnover. Collectively, these findings indicate prodromal impairs memory, potentiates decline likely leading an overproduction cholesterol, interferes compensatory transmission. image

Language: Английский

Citations

16
Behavioral effects of 6-hydroxydopamine-induced damage to nigro-striatal pathway and Locus coeruleus as a rodent model of Parkinson’s disease DOI
Isabella B. Bustelli, Luíz M. Oliveira, Nelson Francisco Correa-Netto

et al.

Behavioural Brain Research, Journal Year: 2024, Volume and Issue: 462, P. 114873 - 114873

Published: Jan. 23, 2024

Language: Английский

Citations

5
Developmental exposure to the Parkinson’s disease-associated organochlorine pesticide dieldrin alters dopamine neurotransmission in α-synuclein pre-formed fibril (PFF)-injected mice DOI Creative Commons
S. Boyd,

Nathan C. Kuhn,

Joseph R. Patterson

et al.

Toxicological Sciences, Journal Year: 2023, Volume and Issue: 196(1), P. 99 - 111

Published: Aug. 22, 2023

Abstract Parkinson’s disease (PD) is the fastest-growing neurological worldwide, with increases outpacing aging and occurring most rapidly in recently industrialized areas, suggesting a role of environmental factors. Epidemiological, post-mortem, mechanistic studies suggest that persistent organic pollutants, including organochlorine pesticide dieldrin, increase PD risk. In mice, developmental dieldrin exposure causes male-specific exacerbation neuronal susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) synucleinopathy. Specifically, α-synuclein (α-syn) pre-formed fibril (PFF) model, leads increased deficits striatal dopamine (DA) turnover motor on challenging beam. Here, we hypothesized alterations DA handling contribute observed changes assessed vesicular monoamine transporter 2 (VMAT2) function release this dieldrin/PFF 2-hit model. Female C57BL/6 mice were exposed 0.3 mg/kg or vehicle every 3 days by feeding, starting at 8 weeks age continuing throughout breeding, gestation, lactation. Male offspring from independent litters underwent unilateral, intrastriatal injections α-syn PFFs 12 age, 3H-DA uptake assays fast-scan cyclic voltammetry performed 4 months post-PFF injection. Dieldrin-induced an slices PFF-injected animals, but no change VMAT2 activity. These results compensatory response synucleinopathy-triggered loss. findings are consistent silent neurotoxicity, where primes nigrostriatal system have exacerbated synucleinopathy absence observable typical markers dysfunction degeneration.

Language: Английский

Citations

12
Photostimulation of Locus Coeruleus CA1 catecholaminergic terminals reversed spatial memory impairment in an Alzheimer's disease mouse model. DOI
Donovan K. Gálvez-Márquez, Oscar Urrego-Morales,

Luis F. Rodríguez-Durán

et al.

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

Abstract Rationale One of the earliest changes associated with Alzheimer's disease (AD) is loss catecholaminergic terminals in cortex and hippocampus originating from Locus Coeruleus (LC). This decline leads to reduced neurotransmitters hippocampus, affecting synaptic plasticity spatial memory. However, it unclear whether restoring transmission LC may alleviate memory deficits AD. Objectives study investigates how optogenetic stimulation projections locus coeruleus hippocampal CA1 region enhance disease. Methods We conducted experiments using a 12-month-old 3xTg-AD mouse model (AD-TH), which expresses Cre recombinase under control tyrosine hydroxylase (TH) gene. allowed us photostimulate before performing two different tasks inducing long-term potentiation (LTP). Results Optogenetic successfully reversed impairment retrieval aging AD-TH mice. Furthermore, this restored neurotransmitter levels enhanced plasticity, as demonstrated by an LTP protocol. Conclusions These findings indicate that circuitry (LC) plays crucial role disrupting contributing seen early stages highlights potential therapeutic benefits targeting neurons improve cognitive function patients

Language: Английский

Citations

0
Regenerating Locus Coeruleus‐Norepinephrine (LC‐NE) Function: A Novel Approach for Neurodegenerative Diseases DOI Creative Commons

Ya-Na Yang,

Yunlong Tao

Cell Proliferation, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

ABSTRACT Pathological changes in the locus coeruleus‐norepinephrine (LC‐NE) neurons, major source of norepinephrine (NE, also known as noradrenaline) brain, are evident during early stages neurodegenerative diseases (ND). Research on both human and animal models have highlighted therapeutic potential targeting LC‐NE system to mitigate progression ND alleviate associated psychiatric symptoms. However, widespread degeneration presents a significant challenge for direct intervention ND. Recent advances regenerative cell therapy offer promising new strategies treatment. The regeneration from pluripotent stem cells (PSCs) could significantly broaden scope LC‐NE‐based therapies In this review, we delve into fundamental background physiological functions LC‐NE. Additionally, systematically examine evidence role neuropathology over recent years. Notably, focus significance PSCs‐derived its impact therapy. A deeper understanding further investigation function pave way practical effective treatments

Language: Английский

Citations

0
tDCS Cranial Nerve Co-Stimulation: Unveiling Brainstem Pathways Involved in Trigeminal Nerve Direct Current Stimulation in Rats DOI Creative Commons
Alireza Majdi, L. Chen, Lars Emil Larsen

et al.

Brain stimulation, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 1, 2025

Language: Английский

Citations

0
Lithium engages autophagy for neuroprotection and neuroplasticity: Translational evidence for therapy DOI
Stefano Puglisi‐Allegra, Gloria Lazzeri, Carla L. Busceti

et al.

Neuroscience & Biobehavioral Reviews, Journal Year: 2023, Volume and Issue: 148, P. 105148 - 105148

Published: March 28, 2023

Language: Английский

Citations

10
Possible role of locus coeruleus neuronal loss in age-related memory and attention deficits DOI Creative Commons
Alessandra Gargano, Bolanle Fatimat Olabiyi, Michela Palmisano

et al.

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: Aug. 24, 2023

Aging is associated with a decline in cognitive abilities, including memory and attention. It generally accepted that age-related histological changes such as increased neuroinflammatory glial activity reduction the number of specific neuronal populations contribute to aging. Noradrenergic neurons locus coeruleus (LC) undergo an approximately 20 % loss during ageing both humans mice, but whether this change contributes deficits not known. To address issue, we asked similar LC young animals observed aged impairs attention, domains are influenced by noradrenergic system impaired For that, treated healthy mice DSP-4, toxin specifically kills neurons. We compared performance DSP-4 models attention memory. do this, first determined dose which causes typical animals. Young showed presence distractor 5-choice serial reaction time test (5-CSRTT). Old, untreated severe 5-CSRTT fear extinction tests. Our data now suggest working greater distractibility attentional tasks extinction. hypothesize moderate aging impairments.

Language: Английский

Citations

9
Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration DOI Open Access
Francesca Biagioni, Michela Ferrucci, Gloria Lazzeri

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3159 - 3159

Published: March 9, 2024

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer’s dementia (AD) and Parkinson’s disease (PD), damage to locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented hypothesized foster onset progression of neurodegeneration within target regions. Specifically, experiments were assess whether selective LC-NE may alter key proteins involved specific limbic regions, hippocampus piriform cortex, compared with dorsal striatum. To achieve this, a loss induced by neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) C57 Black mice, assessed NE dopamine-beta-hydroxylase In these experimental conditions, amount alpha-synuclein (alpha-syn) protein levels increased along alpha-syn expressing neurons cortex. Similar findings obtained concerning phospho-Tau immunoblotting. contrast, decrease inducible HSP70-expressing sequestosome (p62)-expressing cells, at immunoblotting, reported. data provide further understand why AD engagement during PD.

Language: Английский

Citations

3