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Current Issues in Molecular Biology May 2024Astrocytes in the brain contribute to various essential functions, including maintenance of the neuronal framework, survival, communication, metabolic processes, and...
Expression of G2019S LRRK2 in Rat Primary Astrocytes Mediates Neurotoxicity and Alters the Dopamine Synthesis Pathway in N27 Cells via Astrocytic Proinflammatory Cytokines and Neurotrophic Factors.
Astrocytes in the brain contribute to various essential functions, including maintenance of the neuronal framework, survival, communication, metabolic processes, and neurotransmitter levels. Leucine-rich repeat kinase 2 (LRRK2) is associated with the pathogenesis of Parkinson's disease (PD). LRRK2 is expressed in neurons, microglia, and astrocytes and plays diverse roles in these cell types. We aimed to determine the effects of mutant human G2019S-LRRK2 (GS-hLRRK2) in rat primary astrocytes (rASTROs). Transfection with GS-hLRRK2 significantly decreased cell viability compared to transfection with the vector and wild-type human LRRK2 (WT-hLRRK2). GS-hLRRK2 expression significantly reduced the levels of nerve growth factor and increased the levels of proinflammatory cytokines (interleukin-1β and tumor necrosis factor α) compared to the vector and WT-hLRRK2 expression. Furthermore, GS-hLRRK2 expression in rASTROs promoted astrogliosis, which was characterized by increased expression of glial fibrillary acidic protein and vimentin. Treatment with the conditioned medium of G2019S LRRK2-expressing rASTROs decreased N27 cell viability compared to treatment with that of WT-hLRRK2-expressing rASTROs. Consequently, the regulation of the dopamine synthesis pathway was affected in N27 cells, thereby leading to altered levels of tyrosine hydroxylase, dopamine transporter, Nurr1, and dopamine release. Overall, the G2019S LRRK2 mutation disrupted astrocyte function, thereby aggravating PD progression.
PubMed: 38785531
DOI: 10.3390/cimb46050263 -
Behavioural Brain Research Jul 2024Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or...
Both dopamine (DA) and serotonin (5-HT) play key roles in numerous functions including motor control, stress response and learning. So far, there is scarce or conflicting evidence about the effects of 5-HT1A and 5-HT2A receptor (R) agonists and antagonists on recognition memory in the rat. This also holds for their effect on cerebral DA as well as 5-HT release. In the present study, we assessed the effects of the 5-HTR agonist 8-OH-DPAT and antagonist WAY100,635 and the 5-HTR agonist DOI and antagonist altanserin (ALT) on rat behaviors. Moreover, we investigated their impact on monoamine efflux by measuring monoamine transporter binding in various regions of the rat brain. After injection of either 8-OH-DPAT (3 mg/kg), WAY100,635 (0.4 mg/kg), DOI (0.1 mg/kg), ALT (1 mg/kg) or the respective vehicle (saline, DMSO), rats underwent an object and place recognition memory test in the open field. Upon the assessment of object exploration, motor/exploratory parameters and feces excretion, rats were administered the monoamine transporter radioligand N-o-fluoropropyl-2b-carbomethoxy-3b-(4-[I]iodophenyl)-nortropane ([I]-FP-CIT; 8.9 ± 2.6 MBq) into the tail vein. Regional radioactivity accumulations in the rat brain were determined post mortem. Compared vehicle, administration of 8-OH-DPAT impaired memory for place, decreased rearing behavior, and increased ambulation as well as head-shoulder movements. DOI administration led to a reduction in rearing behavior but an increase in head-shoulder motility relative to vehicle. Feces excretion was diminished after ALT relative to vehicle. Dopamine transporter (DAT) binding was increased in the caudateputamen (CP), but decreased in the nucleus accumbens (NAC) after 8-OH-DPAT relative to vehicle. Moreover, DAT binding was decreased in the NAC after ALT relative to vehicle. Findings indicate that 5-HTR inhibition and 5-HTR activation may impair memory for place. Furthermore, results imply associations not only between recognition memory, motor/exploratory behavior and emotionality but also between the respective parameters and the levels of available DA in CP and NAC.
Topics: Animals; Dopamine Plasma Membrane Transport Proteins; Male; Recognition, Psychology; Exploratory Behavior; Rats; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT2A; Motor Activity; Brain; Emotions; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT2 Receptor Agonists; Rats, Wistar
PubMed: 38777263
DOI: 10.1016/j.bbr.2024.115051 -
Acta Neuropathologica Communications May 2024Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial...
Neurodegenerative diseases have common underlying pathological mechanisms including progressive neuronal dysfunction, axonal and dendritic retraction, and mitochondrial dysfunction resulting in neuronal death. The retina is often affected in common neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Studies have demonstrated that the retina in patients with Parkinson's disease undergoes changes that parallel the dysfunction in the brain. These changes classically include decreased levels of dopamine, accumulation of alpha-synuclein in the brain and retina, and death of dopaminergic nigral neurons and retinal amacrine cells leading to gross neuronal loss. Exploring this disease's retinal phenotype and vision-related symptoms is an important window for elucidating its pathophysiology and progression, and identifying novel ways to diagnose and treat Parkinson's disease. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is commonly used to model Parkinson's disease in animal models. MPTP is a neurotoxin converted to its toxic form by astrocytes, transported to neurons through the dopamine transporter, where it causes mitochondrial Complex I inhibition and neuron degeneration. Systemic administration of MPTP induces retinal changes in different animal models. In this study, we assessed the effects of MPTP on the retina directly via intravitreal injection in mice (5 mg/mL and 50 mg/mL to 7, 14 and 21 days post-injection). MPTP treatment induced the reduction of retinal ganglion cells-a sensitive neuron in the retina-at all time points investigated. This occurred without a concomitant loss of dopaminergic amacrine cells or neuroinflammation at any of the time points or concentrations tested. The observed neurodegeneration which initially affected retinal ganglion cells indicated that this method of MPTP administration could yield a fast and straightforward model of retinal ganglion cell neurodegeneration. To assess whether this model could be amenable to neuroprotection, mice were treated orally with nicotinamide (a nicotinamide adenine dinucleotide precursor) which has been demonstrated to be neuroprotective in several retinal ganglion cell injury models. Nicotinamide was strongly protective following intravitreal MPTP administration, further supporting intravitreal MPTP use as a model of retinal ganglion cell injury. As such, this model could be utilized for testing neuroprotective treatments in the context of Parkinson's disease and retinal ganglion cell injury.
Topics: Animals; Retinal Ganglion Cells; Mice, Inbred C57BL; Niacinamide; Neuroprotective Agents; Male; Mice; Administration, Oral; Intravitreal Injections; Disease Models, Animal; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; Parkinsonian Disorders; MPTP Poisoning
PubMed: 38773545
DOI: 10.1186/s40478-024-01782-3 -
Journal of Alzheimer's Disease Reports 2024Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy....
Identifying the coexistence of Lewy body (LB) pathology with Alzheimer's disease (AD) in clinical practice is important in the era of anti-amyloid-β antibody therapy. However, few studies have predicted the presence of comorbid LB pathology with AD using indicative biomarkers of dementia with Lewy bodies or by collecting detailed clinical symptoms. We report the clinical progression of a 67-year-old patient diagnosed with AD who developed rapid eye movement sleep disorder-like symptoms and transient visual hallucinations 10 years after AD onset and was considered to have comorbid LB pathology based on imaging indicative biomarkers of dementia with Lewy bodies.
PubMed: 38746644
DOI: 10.3233/ADR-240019 -
Neurology and Therapy Jun 2024This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical...
This pragmatic review synthesises the current understanding of prodromal dementia with Lewy bodies (pDLB) and prodromal Alzheimer's disease (pAD), including clinical presentations, neuropsychological profiles, neuropsychiatric symptoms, biomarkers, and indications for disease management. The core clinical features of dementia with Lewy bodies (DLB)-parkinsonism, complex visual hallucinations, cognitive fluctuations, and REM sleep behaviour disorder are common prodromal symptoms. Supportive clinical features of pDLB include severe neuroleptic sensitivity, as well as autonomic and neuropsychiatric symptoms. The neuropsychological profile in mild cognitive impairment attributable to Lewy body pathology (MCI-LB) tends to include impairment in visuospatial skills and executive functioning, distinguishing it from MCI due to AD, which typically presents with impairment in memory. pDLB may present with cognitive impairment, psychiatric symptoms, and/or recurrent episodes of delirium, indicating that it is not necessarily synonymous with MCI-LB. Imaging, fluid and other biomarkers may play a crucial role in differentiating pDLB from pAD. The current MCI-LB criteria recognise low dopamine transporter uptake using positron emission tomography or single photon emission computed tomography (SPECT), loss of REM atonia on polysomnography, and sympathetic cardiac denervation using meta-iodobenzylguanidine SPECT as indicative biomarkers with slowing of dominant frequency on EEG among others as supportive biomarkers. This review also highlights the emergence of fluid and skin-based biomarkers. There is little research evidence for the treatment of pDLB, but pharmacological and non-pharmacological treatments for DLB may be discussed with patients. Non-pharmacological interventions such as diet, exercise, and cognitive stimulation may provide benefit, while evaluation and management of contributing factors like medications and sleep disturbances are vital. There is a need to expand research across diverse patient populations to address existing disparities in clinical trial participation. In conclusion, an early and accurate diagnosis of pDLB or pAD presents an opportunity for tailored interventions, improved healthcare outcomes, and enhanced quality of life for patients and care partners.
PubMed: 38720013
DOI: 10.1007/s40120-024-00620-x -
NeuroImmune Pharmacology and... Mar 2024HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the...
OBJECTIVES
HIV-1 Tat (transactivator of transcription) protein disrupts dopaminergic transmission and potentiates the rewarding effects of cocaine. Allosteric modulators of the dopamine transporter (DAT) have been shown to reverse Tat-induced DAT dysfunction. We hypothesized that a novel DAT allosteric modulator, SRI-30827, would counteract Tat-induced potentiation of cocaine reward.
METHODS
Doxycycline (Dox)-inducible Tat transgenic (iTat-tg) mice and their G-tg (Tat-null) counterparts were tested in a cocaine conditioned place preference (CPP) paradigm. Mice were treated 14 days with saline, or Dox (100 mg/kg/day, i.p.) to induce Tat protein. Upon induction, mice were place conditioned two days with cocaine (10 mg/kg/day) after a 1-h daily intracerebroventricular (i.c.v.) pretreatment with SRI-30827 (1 nmol) or a vehicle control, and final place preference assessed as a measure of cocaine reward.
RESULTS
Dox-treatment significantly potentiated cocaine-CPP in iTat-tg mice over the response of saline-treated control littermates. SRI-30827 treatment eliminated Tat-induced potentiation without altering normal cocaine-CPP in saline-treated mice. Likewise, SRI-30827 did not alter cocaine-CPP in both saline- and Dox-treated G-tg mice incapable of expressing Tat protein.
CONCLUSIONS
These findings add to a growing body of evidence that allosteric modulation of DAT could provide a promising therapeutic intervention for patients with comorbid HIV-1 and cocaine use disorder (CUD).
PubMed: 38711842
DOI: 10.1515/nipt-2023-0022 -
Frontiers in Neurology 2024Diagnosing Dementia with Lewy Bodies (DLB) remains a challenge in clinical practice. The use of I-ioflupane (DaTscan) SPECT imaging, which detects reduced dopamine... (Review)
Review
BACKGROUND
Diagnosing Dementia with Lewy Bodies (DLB) remains a challenge in clinical practice. The use of I-ioflupane (DaTscan) SPECT imaging, which detects reduced dopamine transporter (DAT) uptake-a key biomarker in DLB diagnosis-could improve diagnostic accuracy. However, DAT imaging is underutilized despite its potential, contributing to delays and suboptimal patient management.
METHODS
This review evaluates DLB diagnostic practices and challenges faced within the U.S. by synthesizing information from current literature, consensus guidelines, expert opinions, and recent updates on DaTscan FDA filings. It contrasts DAT SPECT with alternative biomarkers, provides recommendations for when DAT SPECT imaging may be indicated and discusses the potential of emerging biomarkers in enhancing diagnostic approaches.
RESULTS
The radiopharmaceutical I-ioflupane for SPECT imaging was initially approved in Europe (2000) and later in the US (2011) for Parkinsonism/Essential Tremor. Its application was extended in 2022 to include the diagnosis of DLB. DaTscan's diagnostic efficacy for DLB, with its sensitivity, specificity, and predictive values, confirms its clinical utility. However, US implementation faces challenges such as insurance barriers, costs, access issues, and regional availability disparities.
CONCLUSION
I-ioflupane SPECT Imaging is indicated for DLB diagnosis and differential diagnosis of Alzheimer's Disease, particularly in uncertain cases. Addressing diagnostic obstacles and enhancing physician-patient education could improve and expedite DLB diagnosis. Collaborative efforts among neurologists, geriatric psychiatrists, psychologists, and memory clinic staff are key to increasing diagnostic accuracy and care in DLB management.
PubMed: 38711561
DOI: 10.3389/fneur.2024.1395413 -
NPJ Parkinson's Disease May 2024Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms...
Resilience in neuroscience generally refers to an individual's capacity to counteract the adverse effects of a neuropathological condition. While resilience mechanisms in Alzheimer's disease are well-investigated, knowledge regarding its quantification, neurobiological underpinnings, network adaptations, and long-term effects in Parkinson's disease is limited. Our study involved 151 Parkinson's patients from the Parkinson's Progression Marker Initiative Database with available Magnetic Resonance Imaging, Dopamine Transporter Single-Photon Emission Computed Tomography scans, and clinical information. We used an improved prediction model linking neuropathology to symptom severity to estimate individual resilience levels. Higher resilience levels were associated with a more active lifestyle, increased grey matter volume in motor-associated regions, a distinct structural connectivity network and maintenance of relative motor functioning for up to a decade. Overall, the results indicate that relative maintenance of motor function in Parkinson's patients may be associated with greater neuronal substrate, allowing higher tolerance against neurodegenerative processes through dynamic network restructuring.
PubMed: 38697984
DOI: 10.1038/s41531-024-00699-x -
EJNMMI Radiopharmacy and Chemistry May 2024Parkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission...
BACKGROUND
Parkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission tomography (PET) imaging has emerged as a powerful and non-invasive method to quantify dopaminergic function in the living brain. The PET radioligand, [F]FE-PE2I, a cocaine chemical derivative, has shown promising properties for in vivo PET imaging of DAT, including high affinity and selectivity for DAT, excellent brain permeability, and favorable metabolism. The aim of the current study was to scale up the production of [F]FE-PE2I to fulfil the increasing clinical demand for this tracer.
RESULTS
Thus, a fully automated and GMP-compliant production procedure has been developed using a commercially available radiosynthesis module GE TRACERLab FX2 N. [F]FE-PE2I was produced with a radiochemical yield of 39 ± 8% (n = 4, relative [F]F delivered to the module). The synthesis time was 70 min, and the molar activity was 925.3 ± 763 GBq/µmol (250 ± 20 Ci/µmol). The produced [F]FE-PE2I was stable over 6 h at room temperature.
CONCLUSION
The protocol reliably provides a sterile and pyrogen-free GMP-compliant product.
PubMed: 38696063
DOI: 10.1186/s41181-024-00269-9 -
Cellular and Molecular Life Sciences :... May 2024Glial cells constitute nearly half of the mammalian nervous system's cellular composition. The glia in C. elegans perform majority of tasks comparable to those conducted...
Glial cells constitute nearly half of the mammalian nervous system's cellular composition. The glia in C. elegans perform majority of tasks comparable to those conducted by their mammalian equivalents. The cephalic sheath (CEPsh) glia, which are known to be the counterparts of mammalian astrocytes, are enriched with two nuclear hormone receptors (NHRs)-NHR-210 and NHR-231. This unique enrichment makes the CEPsh glia and these NHRs intriguing subjects of study concerning neuronal health. We endeavored to assess the role of these NHRs in neurodegenerative diseases and related functional processes, using transgenic C. elegans expressing human alpha-synuclein. We employed RNAi-mediated silencing, followed by behavioural, functional, and metabolic profiling in relation to suppression of NHR-210 and 231. Our findings revealed that depleting nhr-210 changes dopamine-associated behaviour and mitochondrial function in human alpha synuclein-expressing strains NL5901 and UA44, through a putative target, pgp-9, a transmembrane transporter. Considering the alteration in mitochondrial function and the involvement of a transmembrane transporter, we performed metabolomics study via HR-MAS NMR spectroscopy. Remarkably, substantial modifications in ATP, betaine, lactate, and glycine levels were seen upon the absence of nhr-210. We also detected considerable changes in metabolic pathways such as phenylalanine, tyrosine, and tryptophan biosynthesis metabolism; glycine, serine, and threonine metabolism; as well as glyoxalate and dicarboxylate metabolism. In conclusion, the deficiency of the nuclear hormone receptor nhr-210 in alpha-synuclein expressing strain of C. elegans, results in altered mitochondrial function, coupled with alterations in vital metabolite levels. These findings underline the functional and physiological importance of nhr-210 enrichment in CEPsh glia.
Topics: Animals; Caenorhabditis elegans; Mitochondria; Neuroglia; Parkinson Disease; Humans; alpha-Synuclein; Disease Models, Animal; Caenorhabditis elegans Proteins; Animals, Genetically Modified; Receptors, Cytoplasmic and Nuclear; Dopamine; Metabolomics; RNA Interference
PubMed: 38691171
DOI: 10.1007/s00018-024-05179-2