Aging and MPTP-sensitivity depend on molecular and ultrastructural signatures of astroglia and microglia in mice substantia nigra (original) (raw)
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Research Square (Research Square), 2023
Opposing phenomena of both oligodendrogliosis and oligodendroglial degeneration is reported in the striatum of MPTP-injected mice model of Parkinson's disease (PD); reducing the clarity on their contribution to PD pathology. Furthermore, the role of oligodendroglia of substantia nigra pars compacta (SNpc), in pathogenesis and differential susceptibility to PD, is not known. In our earlier study, the MPTPsensitive young C57BL/6J showed loss of 50-60% of SNpc neurons following MPTP, whereas the MPTPresistant CD-1 showed a loss of 15-17%, suggesting better neuroprotection in the latter. We now investigate the effects of age and MPTP on oligodendroglial and myelin sheath ultrastructure, in SNpc, by electron microscopy as well as myelin-associated protein CNPase by semi-quantitative confocal microscopy and immunoblotting. MPTP-induced mitochondrial shrinkage suggests toxicity to mitochondria and dilation of Golgi-complex saccules indicates protein packaging de cits, in the oligodendroglia of young C57BL/6J. Contrariwise in CD-1, presence of elongated mitochondria and multiple polyribosomes may suggest preserved ultrastructure. The organelles were affected at middle age in C57BL/6J but at old age in CD-1. The neuropil of SNpc in both strains harbored unmyelinated and lightly myelinated bers. The enhanced density of myelin bers following MPTP, suggests re-myelination of surviving neurons. MPTP aggravated myelin decompaction at middle age in C57BL/6J, but at old age in CD-1. Upregulation of CNPase in MPTP-injected middle-aged CD-1 suggests attempt at compensation. Thus, oligodendroglia of the MPTPsensitive strain shows degenerative features, while those of MPTP-resistant strain show compensatory capabilities against neuroin ammatory milieu; till middle age. It is pertinent to reconsider oligodendroglial involvement in PD.
Neurobiology of Aging, 2015
Age being a risk factor for Parkinson's disease, assessment of age-related changes in the human substantia nigra may elucidate its pathogenesis. Increase in Marinesco bodies, a-synuclein, free radicals and so forth in the aging nigral neurons are clear indicators of neurodegeneration. Here, we report the glial responses in aging human nigra. The glial numbers were determined on Nissl-stained sections. The expression of glial fibrillary acidic protein, S100b, 2 0 , 3 0 -cyclic nucleotide 3 0 phosphodiesterase, and Iba1 was assessed on cryosections of autopsied midbrains by immunohistochemistry and densitometry. The glial counts showed a biphasic increase, of which, the first prominent phase from fetal age to birth could be physiological gliogenesis whereas the second one after middle age may reflect mild age-related gliosis. Astrocytic morphology was altered, but glial fibrillary acidic protein expression increased only mildly. Presence of type-4 microglia suggests possibility of neuroinflammation. Mild reduction in 2 0 , 3 0cyclic nucleotide 3 0 phosphodiesteraseelabeled area denotes subtle demyelination. Stable age-related S100b expression indicates absence of calcium overload. Against the expected prominent gliosis, subtle age-related morphological alterations in human nigral glia attribute them a participatory role in aging.
Role of Microglia in Parkinson
2014
Parkinson's disease (PD) is the most common neurodegenerative movement disorder (Schapira, 2009). It is mainly characterized by the progressive loss of dopaminergic (DA) neurons in the substantianigra pars compacta (SNpc) in the midbrain, which translates into typical motor symptoms collectively known as Parkinsonism (Gelb et al., 1999).Just as in most chronic and acute neurodegenerative conditions, the pathological features in PD are accompanied by inflammation and microglia activation. Microglia function as the brain's immune cells and thus are essential to the proper functioning of the central nervous system (CNS). However the activation of microglia, when chronic, is considered neurotoxic and can lead to neuronal dysfunction and death (McGeer et al., 1988).For long it has been questioned whether microglial activation in PD is a cause or consequence of the PD pathology, and particularly of the loss of dopaminergic neurons in the SNpc.In this review, we discuss the role of microglia in the pathological features characteristic of PD. We propose that microglia constitute a secondary causal mechanism in PD and act through a vicious cycle of inflammation. Mounting epidemiological and clinical evidence indeed suggests that chronic microglial activation occurs early in the disease and contributes to the demise of dopaminergic neuron. Furthermore, neurotoxin animal models have helped elucidate several molecular mechanisms thought to regulate this inflammation. If microglia do in fact contribute to the disease pathology, then understanding these mechanisms can be valuable for therapeutic treatments in PD.
Experimental Neurology, 2012
Parkinson disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra (SN). Recent evidence suggests that innate and adaptive immune responses can influence dopaminergic cell death in animal models of PD. However, the precise role of mononuclear phagocytes, key players in damaged tissue clearance and cross-talk with cells of adaptive immune system, remains open in PD. Mononuclear phagocytes in the brain occur as brain-resident microglia and as brain-infiltrating myeloid cells. To elucidate their differential contribution in the uptake of dopaminergic cell debris and antigen presentation capacity, we labeled nigral dopaminergic neurons retrogradely with inert rhodamine-conjugated latex retrobeads before inducing their degeneration by subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. We used green fluorescent protein (GFP)-expressing bone marrow chimeric mice to differentiate braininfiltrating from brain-resident myeloid cells. We found that half of both endogenous (GFP−) and exogenous (GFP +) microglia (Iba1 +) in the SN incorporated the tracer from degenerating dopaminergic neurons 1d after MPTP intoxication. In absolute numbers, endogenous microglia were much more activated to macrophages compared to exogenous myeloid cells at 1d after MPTP. Mainly the endogenous, tracerphagocytosing microglia expressed the major histocompatibility complex (MHC) class II molecule for antigen presentation. Additionally, T-lymphocytes (Iba1−/GFP+/CD3 +), which infiltrate the MPTP-lesioned SN, were mainly in direct contact with MHCII + endogenous microglia. Our data suggest that brain-resident microglia are predominantly implicated in the removal of dopaminergic cell debris and the cross-talk with infiltrating T-lymphocytes in the SN in the MPTP mouse model of PD.
Inflammation Research, 2009
Objective The aim of the present study was to determine how aging and gender influence the response of astrocytes to 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP) intoxication. Materials and methods To asses the MPTP-induced astrocytes activation in nigro-striatal system, we measured the temporal changes in mRNA and protein expression of the specific astrocytic marker, glial fibrillary acidic protein (GFAP; by RT-PCR and Western blot), in the striatum of male and female C57BL/6 mice (2 and 12-month old) after 6 h and 1, 3, 7, 14 and 21 days post-intoxication. Results We observed the increases of GFAP mRNA level post-MPTP intoxication in both young and aging males only at early time points, whereas in females (both ages) also at later time points. We noticed maximal increase of GFAP protein content on the 3rd day post-intoxication in young and aged males, whereas in females at the 7-day time point. Conclusions The present results provide additional information of potential relevance to understand the mechanisms of gender and age-related difference in susceptibility of nigro-striatal system to MPTP insult.
Antioxidants
Parkinson’s disease (PD) is a chronic and progressive age-related neurodegenerative disease affecting up to 3% of the global population over 65 years of age. Currently, the underlying physiological aetiology of PD is unknown. However, the diagnosed disorder shares many common non-motor symptoms associated with ageing-related neurodegenerative disease progression, such as neuroinflammation, microglial activation, neuronal mitochondrial impairment, and chronic autonomic nervous system dysfunction. Clinical PD has been linked to many interrelated biological and molecular processes, such as escalating proinflammatory immune responses, mitochondrial impairment, lower adenosine triphosphate (ATP) availability, increasing release of neurotoxic reactive oxygen species (ROS), impaired blood brain barrier integrity, chronic activation of microglia, and damage to dopaminergic neurons consistently associated with motor and cognitive decline. Prodromal PD has also been associated with orthostati...
Hippocampal proliferation is increased in presymptomatic Parkinson's disease and due to microglia
Neural plasticity, 2014
Besides dopamine-deficiency related motor symptoms, nonmotor symptoms, including cognitive changes occur in Parkinson's disease (PD) patients, that may relate to accumulation of α-synuclein in the hippocampus (HC). This brain region also contains stem cells that can proliferate. This is a well-regulated process that can, for example, be altered by neurodegenerative conditions. In contrast to proliferation in the substantia nigra and subventricular zone, little is known about the HC in PD. In addition, glial cells contribute to neurodegenerative processes and may proliferate in response to PD pathology. In the present study, we questioned whether microglial cells proliferate in the HC of established PD patients versus control subjects or incidental Lewy body disease (iLBD) cases as a prodromal state of PD. To this end, proliferation was assessed using the immunocytochemical marker minichromosome maintenance protein 2 (MCM2). Colocalization with Iba1 was performed to determine mic...
Emerging roles of microglial activation and non-motor symptoms in Parkinson's disease
Progress in Neurobiology, 2012
Recent data has indicated that the traditional view of Parkinson's disease (PD) as an isolated disorder of the nigrostriatal dopaminergic system alone is an oversimplification of its complex symptomatology. Aside from classical motor deficits, various non-motor symptoms including autonomic dysfunction, sensory and cognitive impairments as well as neuropsychiatric alterations and sleep disturbances are common in PD. Some of these non-motor symptoms can even antedate the motor problems. Many of them are associated with extranigral neuropathological changes, such as extensive a-synuclein pathology and also neuroinflammatory responses in specific brain regions, i.e. microglial activation, which has been implicated in several aspects of PD pathogenesis and progression. However, microglia do not represent a uniform population, but comprise a diverse group of cells with brain region-specific phenotypes that can exert beneficial or detrimental effects, depending on the local phenotype and context. Understanding how microglia can be neuroprotective in one brain region, while promoting neurotoxicity in another, will improve our understanding of the role of microglia in neurodegeneration in general, and of their role in PD pathology in particular. Since neuroinflammatory responses are in principle modifiable, such approaches could help to identify new targets or adjunctive therapies for the full spectrum of PD-related symptoms.