<scp>HIV</scp>‐1<scp>T</scp>at regulation of dopamine transmission and microglial reactivity is brain region specific

Miller, Douglas R.; Shaerzadeh, Fatemeh; Phan, Leah T.; Sharif, Nesrin; Gamble-George, Joyonna; McLaughlin, Jay P.; Streit, Wolfgang J.; Khoshbouei, Habibeh

doi:10.1002/glia.23447

Cited by 14 publications

(11 citation statements)

References 94 publications

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“…High doses of METH promote microglial activation (Thomas et al, 2004;Fantegrossi et al, 2008). Surprisingly, microglial activation can occur before the onset of pathology (LaVoie et al, 2004), reinforcing the notion of their sensitivity to homeostatic disturbances such as neuronal loss (Miller et al, 2018).…”

Section: Microgliamentioning

confidence: 81%

Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity

Miller

Gopinath

et al. 2021

J Pharmacol Exp Ther

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Methamphetamine (METH) is a potent psychostimulant that increases extracellular monoamines such as dopamine and norepinephrine and affects multiple tissue and cell types in the CNS and peripheral immune cells. The reinforcing properties of METH underlie its significant abuse potential and dysregulation of peripheral immunity and central nervous system functions. Together, the constellation of METH's effects on cellular targets and regulatory processes has led to immune suppression and neurodegeneration in METH addicts and animal models of METH exposure. Here we extensively review many of the cell types and mechanisms of METH-induced dysregulation of the central nervous and peripheral immune systems. Significance StatementEmerging research has begun to show that methamphetamine regulates dopaminergic neuronal activity. In addition, METH affects non-neuronal brain cells, such as microglia and astrocytes, and immunological cells of the periphery. Concurrent disruption of bidirectional communication between dopaminergic neurons and glia in the CNS and peripheral immune cell dysregulation gives rise to a constellation of dysfunctional neuronal, cell, and tissue types. Therefore, understanding the pathophysiology of METH requires consideration of the multiple targets at the interface between basic and clinical neuroscience.

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Section: Microgliamentioning

confidence: 81%

Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity

Miller

Gopinath

et al. 2021

J Pharmacol Exp Ther

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“…First, dopaminergic neurons have a large axonal projection area, which may span different brain regions [ 57 , 58 ]. Second, it is a common observation in multiple neurodegeneration diseases that TH may lose immunoreactivity without a concomitant loss of dopamine neurons [ 59 , 60 ]. Next, the dopamine transporter (DAT), which reuptakes presynaptic dopamine neurons at the synapse, is detectable only in about half of the ventral tegmental neurons [ 61 ].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies

Zhang

Qiu

et al. 2022

BMC Neurosci

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Background Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are common age-related neurodegenerative diseases comprising Lewy body spectrum disorders associated with cortical and subcortical Lewy body pathology. Over 30% of PD patients develop PD dementia (PDD), which describes dementia arising in the context of established idiopathic PD. Furthermore, Lewy bodies frequently accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer’s disease (AD), where they are observed in the amygdala of approximately 60% of sporadic and familial AD. While PDD and DLB share similar pathological substrates, they differ in the temporal onset of motor and cognitive symptoms; however, protein markers to distinguish them are still lacking. Methods Here, we systematically studied a series of AD and PD pathogenesis markers, as well as mitochondria, mitophagy, and neuroinflammation-related indicators, in the substantia nigra (SN), temporal cortex (TC), and caudate and putamen (CP) regions of human post-mortem brain samples from individuals with PDD and DLB and condition-matched controls. Results We found that p-APPT668 (TC), α-synuclein (CP), and LC3II (CP) are all increased while the tyrosine hydroxylase (TH) (CP) is decreased in both PDD and DLB compared to control. Also, the levels of Aβ42 and DD2R, IBA1, and p-LRRK2S935 are all elevated in PDD compared to control. Interestingly, protein levels of p-TauS199/202 in CP and DD2R, DRP1, and VPS35 in TC are all increased in PDD compared to DLB. Conclusions Together, our comprehensive and systematic study identified a set of signature proteins that will help to understand the pathology and etiology of PDD and DLB at the molecular level.

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“…TH, Iba1, and HuC/D immunolabeled cells were counted at a ×20 magnification in the z-axis. Sampling grid sizes and counting frames (80 × 80 μm) were used in order to have a Gundersen coefficient error of 0.1 or less (Banuelos et al, 2013;Miller et al, 2018). TH positive neurons were included if the cytoplasm of the cell was clearly labeled and contained an unstained nucleus.…”

Section: Stereological Analysismentioning

confidence: 99%

Microglia senescence occurs in both substantia nigra and ventral tegmental area

Shaerzadeh

Phan

Miller

et al. 2020

Glia

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During aging humans lose midbrain dopamine neurons, but not all dopamine regions exhibit vulnerability to neurodegeneration. Microglia maintain tissue homeostasis and neuronal support, but microglia become senescent and likely lose some of their functional abilities. Since aging is the greatest risk factor for Parkinson's disease, we hypothesized that aging‐related changes in microglia and neurons occur in the vulnerable substantia nigra pars compacta (SNc) but not the ventral tegmental area (VTA). We conducted stereological analyses to enumerate microglia and dopaminergic neurons in the SNc and VTA of 1‐, 6‐, 9‐, 18‐, and 24‐month‐old C57BL/J6 mice using sections double‐stained with tyrosine hydroxylase (TH) and Iba1. Both brain regions show an increase in microglia with aging, whereas numbers of TH+ cells show no significant change after 9 months of age in SNc and 6 months in VTA. Morphometric analyses reveal reduced microglial complexity and projection area while cell body size increases with aging. Contact sites between microglia and dopaminergic neurons in both regions increase with aging, suggesting increased microglial support/surveillance of dopamine neurons. To assess neurotrophin expression in dopaminergic neurons, BDNF and TH mRNA were quantified. Results show that the ratio of BDNF to TH decreases in the SNc, but not the VTA. Gait analysis indicates subtle, aging‐dependent changes in gait indices. In conclusion, increases in microglial cell number, ratio of microglia to dopamine neurons, and contact sites suggest that innate biological mechanisms compensate for the aging‐dependent decline in microglia morphological complexity (senescence) to ensure continued neuronal support in the SNc and VTA.

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HIV‐1Tat regulation of dopamine transmission and microglial reactivity is brain region specific

Cited by 14 publications

References 94 publications

Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity

Methamphetamine Dysregulation of the Central Nervous System and Peripheral Immunity

Increased expression of pathological markers in Parkinson’s disease dementia post-mortem brains compared to dementia with Lewy bodies

Microglia senescence occurs in both substantia nigra and ventral tegmental area

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