Bidirectional Regulation of Cognitive and Anxiety-like Behaviors by Dentate Gyrus Mossy Cells in Male and Female Mice

The dentate gyrus (DG) of the hippocampus is important for cognition and behavior. However, the circuits underlying these functions are unclear. DG mossy cells (MCs) are potentially important because of their excitatory synapses on the primary cell type, granule cells (GCs). However, MCs also activate GABAergic neurons, which inhibit GCs. We used viral delivery of designer receptors exclusively activated by designer drugs (DREADDs) in mice to implement a gain- and loss-of-function study of MCs in diverse behaviors. Using this approach, manipulations of MCs could bidirectionally regulate behavior. The results suggest that inhibiting MCs can reduce anxiety-like behavior and improve cognitive performance. However, not all cognitive or anxiety-related behaviors were influenced, suggesting specific roles of MCs in some, but not all, types of cognition and anxiety. Notably, several behaviors showed sex-specific effects, with females often showing more pronounced effects than the males. We also used the immediate early gene c-Fos to address whether DREADDs bidirectionally regulated MC or GC activity. We confirmed excitatory DREADDs increased MC c-Fos. However, there was no change in GC c-Fos, consistent with MC activation leading to GABAergic inhibition of GCs. In contrast, inhibitory DREADDs led to a large increase in GC c-Fos, consistent with a reduction in MC excitation of GABAergic neurons, and reduced inhibition of GCs. Together, these results suggest that MCs regulate anxiety and cognition in specific ways. We also raise the possibility that cognitive performance may be improved by reducing anxiety.SIGNIFICANCE STATEMENT The dentate gyrus (DG) has many important cognitive roles as well as being associated with affective behavior. This study addressed how a glutamatergic DG cell type called mossy cells (MCs) contributes to diverse behaviors, which is timely because it is known that MCs regulate the activity of the primary DG cell type, granule cells (GCs), but how MC activity influences behavior is unclear. We show, surprisingly, that activating MCs can lead to adverse behavioral outcomes, and inhibiting MCs have an opposite effect. Importantly, the results appeared to be task-dependent and showed that testing both sexes was important. Additional experiments indicated what MC and GC circuitry was involved. Together, the results suggest how MCs influence behaviors that involve the DG.     

Loss of TREM2 Confers Resilience to Synaptic and Cognitive Impairment in Aged Mice

Triggering receptor expressed on myeloid cells 2 (TREM2), a receptor exclusively expressed by microglia in the brain, modulates microglial immune homeostasis. Human genetic studies have shown that the loss-of-function mutations in TREM2 signaling are strongly associated with an elevated risk of age-related neurodegenerative diseases including Alzheimer''s disease (AD). Numerous studies have investigated the impact of TREM2 deficiency in the pathogenic process of AD. However, the role of TREM2 in shaping neuronal and cognitive function during normal aging is underexplored. In the present study, we employed behavioral, electrophysiological, and biochemical approaches to assess cognitive and synaptic function in male and female young and aged TREM2-deficient (Trem2−/−) mice compared with age-matched, sex-matched, and genetic background-matched wild-type (WT) C57BL/6J controls. Young Trem2−/− mice exhibited normal cognitive function and synaptic plasticity but had increased dendritic spine density compared with young WT. Unexpectedly, aged Trem2−/− mice showed superior cognitive performance compared with aged WT controls. Consistent with the behavioral data, aged Trem2−/− mice displayed significantly enhanced hippocampal long-term potentiation (LTP) and increased dendritic spine density and synaptic markers compared with aged WT mice. Taken together, these findings suggest that loss of TREM2 affects the neuronal structure and confers resilience to age-related synaptic and cognitive impairment during non-pathogenic aging.SIGNIFICANCE STATEMENT Microglia are innate immune cells of the brain that orchestrates neurodevelopment, synaptic function, and immune response to environmental stimuli. Microglial triggering receptor expressed on myeloid cells 2 (TREM2) signaling plays pivotal roles in regulating these functions and loss of TREM2 signaling leads to increased risk of developing age-related neurologic disorders. However, the neurologic role of TREM2 in normal aging is poorly understood. The results of the present study unveil the positive impacts of TREM2 deficiency on cognitive and synaptic function during aging and suggest that TREM2 may exert detrimental effects on neuronal function. The possibility of age-related negative impacts from TREM2 is critically important since TREM2 has emerged as a major therapeutic target for Alzheimer''s dementia.     

GABA(A) and mu-opioid receptor binding in the globus pallidus and endopeduncular nucleus of animals symptomatic for and recovered from experimental Parkinsonism

The expression of parkinsonian motor symptoms may be partly attributed to an increase in GABAergic neurotransmission from hyperactive GABA/enkephalinergic striatopallidal efferents. The present study measured pallidal GABA_A and μ-opioid receptor binding in normal cats and cats symptomatic for and recovered from MPTP-induced parkinsonism. GABA_A receptor binding was significantly decreased in the globus pallidus (GP) in symptomatic cats and returned to normal levels in spontaneously recovered cats. Mu-opioid receptor binding in the GP was significantly decreased in symptomatic cats and remained significantly decreased in recovered cats. These results suggest that GABA_A but not μ-opioid receptor binding may correlate with the expression of parkinsonian motor deficits and may reflect increased pallidal GABA and ENK release in parkinsonian animals. Upon recovery from experimental parkinsonism, however, pallidal GABA_A receptor binding returns to normal levels while μ-opioid receptor binding reflecting enkephalin release remains elevated.     

Acute and repeated treatment with L-DOPA increase c-jun expression in the 6-hydroxydopamine-lesioned forebrain of rats and common marmosets

L-DOPA was acutely or repeatedly administered to rats and common marmosets (Callithrix jacchus) with unilateral 6-hydroxydopamine (6-OHDA) denervation of the dopamine inputs to the forebrain. Using in situ hybridization it was found that L-DOPA-treated animals exhibited a pronounced induction in the gene expression of both c-jun and c-fos in striatum and cerebral cortex restricted to the dopamine-depleted hemisphere. In contrast, acute treatment with cocaine induced c-fos mRNA, but not c-jun mRNA, in the striatum of normal animals. These data suggest that dopamine denervation leads to neurochemical adaptations which enables L-DOPA to induce a sustained gene expression of c-jun. Such aberrant gene regulation may underlie the development of L-DOPA-induced movement disorders which are commonly found in patients with Parkinson's disease.     

Organization of dopamine D1 and D2 receptors in human striatum: receptor autoradiographic studies in Huntington's disease and schizophrenia

The technique of quantitative autoradiography was used to examine the effects of Huntington's disease (HD) and schizophrenia on the organization of striatal dopamine (DA) D1 and D2 receptors. Whereas the striatum of HD cases showed a reduction in the density of D1 ([3H]SCH 23390) and D2 ([3H]spiroperidol) receptors, the patterning of D2 receptor loss did not match that of the D1 receptor loss. The HD loss of D1 D1 receptors (65%) is far greater than the loss of D2 receptors (28%). Whereas there was a dorsal-ventral gradient of effect on both receptor subtypes, the effects of HD on D2 receptors in the ventral putamen (PUT) and nucleus accumben septi (NAS) were minimal. Similarly, muscarinic M1 and M2 receptors demonstrate different patterns of alteration in HD. The M2 subtype, labeled with [3H]N-methylscopolamine (in the presence of excess pirenzepine to occlude M1 sites), was depleted far more than the M1 receptor subtype, labeled with [3H]pirenzepine. Although the effects of HD on [3H]mazindol labeling of DA terminals were more heterogeneous, there appeared to be a relative preservation of this afferent input to the striatum of the HD cases. In the schizophrenic cases, our autoradiographic studies confirm previous reports of an elevation of D2 receptor density in the striata of many schizophrenics. This increase was evident even though two of the three cases were known to have not been treated with neuroleptics, and the third case may also have been drug naive. However, the increase was far greater in the NAS (164%) and ventral PUT (173%) than more dorsally in the striatum (68%). The density of D1 receptors and DA terminals labeled with [3H]mazindol in the striatum of schizophrenics was not significantly different from that of control cases. Thus in both HD and schizophrenia, the ratio of D2/D1 receptors is altered in favor of the D2 population, particularly in the NAS.     

Association study between the LINGO1 gene and Parkinson's disease in the Italian population

Some studies have suggested an overlap of clinical and genetic findings between essential tremor (ET) and Parkinson’s disease (PD). The first genome-wide association study in ET showed a significant association with the rs9652490 SNP of the leucine-rich repeat and Ig domain containing 1 (LINGO1) gene. Since patients with PD have higher LINGO1 expression levels compared to healthy controls, and animal models of PD show elevated LINGO1 protein levels after experimentally induced damage in the striatum, it can be inferred that LINGO1 is probably involved in PD pathophysiology.In this study, we performed a genetic association analysis of the rs9652490 and rs11856808 SNPs in Italian PD patients and controls to assess the role of these variants in our population. A total of 567 patients with PD and 468 control subjects were enrolled in five Movement Disorder centers located in Central-Southern Italy. Both variants were significantly associated with PD under a recessive model of inheritance before applying the Bonferroni correction. The GG genotype of rs9652490 and the TT genotype of rs11856808 were less frequent in patients than in controls, suggesting a protective effect against the disease. However, after stringent correction, only the P-values obtained from allele and genotype comparisons of the rs11856808 SNP remained significant. Our findings suggest that LINGO1 plays a certain role in the development of PD in the Italian population and represents an interesting candidate gene responsible for PD, due to its involvement in neurological processes.     

Distribution and ultrastructural localization of torsinA immunoreactivity in the human brain

We have examined the distribution and ultrastructural localization of torsinA, the protein product of the TOR1A gene, in the normal adult human and Macaque brain. TorsinA immunoreactivity was visualized using a monoclonal antibody raised against a fusion protein encoding exon 4 of human torsinA. Western blot analysis of brain homogenates revealed a major species of about 39 kDa, consistent with the predicted size of glycosylated torsinA protein. By light microscopy, torsinA like-immunoreactivity was enriched in gray matter in all brain regions examined. Immunoreactivity was concentrated in the neuropil and immunopositive cell bodies were not observed. Structures particularly enriched in torsinA like-immunoreactivity included the cerebral cortex, the caudate-putamen, globus pallidus, the hippocampal formation, the thalamus, the substantia nigra and molecular cell layer of the cerebellar cortex. Cell bodies of pigmented dopamine neurons in the substantia nigra pars compacta were immunonegative. Biochemical fractionation of the human striata revealed a concentration of torsinA immunoreactivity in particulate fractions. Ultrastructural studies of the human and Macaque striata further revealed an association of torsinA immunostaining with small vesicles within axons and presynaptic terminals forming symmetric synapses. These ultrastructural studies are consistent with a pre-synaptic localization of torsinA protein in the adult striatum and are consistent with a role of torsinA in modulating striatal signaling, although the widespread localization of the protein suggests it probably also participates in signaling in other regions.     

Sex Steroid Levels and AD‐Like Pathology in 3xTgAD Mice

Decreases in testosterone and 17β‐oestradiol (E₂) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in β‐amyloid and tau pathological lesions. Although recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD‐like pathology, almost none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age‐related changes in testosterone and E₂ concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and nontransgenic (ntg) mice. We report for the first time that circulating and brain testosterone levels significantly increase in male 3xTgAD mice with age, but without changes in AR‐immunoreactive (IR) cell number in the hippocampal CA1 or medial amygdala. The age‐related increase in hippocampal testosterone levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over‐expression of human tau up‐regulate the hypothalamic‐pituitary‐gonadal axis in these mice. Although circulating and brain E₂ levels remained stable with age in both male and female 3xTgAD and ntg mice, ER‐IR cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Furthermore, E₂ levels were significantly higher in the hippocampus than in serum, suggesting local production of E₂. Although triple transgenic mice mimic AD‐like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions.     

Dopamine receptor D2 on CD4+ T cells is protective against neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease

Parkinson's disease (PD) is a chronic neurodegenerative disease. Recently, neuroinflammation driven by CD4⁺ T cells has been involved in PD pathophysiology. Human and murine lymphocytes express all the five subtypes of dopamine receptors (DRs), DRD1 to DRD5. However, roles of DRs particularly DRD2 expressed on CD4⁺ T cells in PD remain elucidated. Global Drd1- or Drd2-knockout (Drd1^−/− or Drd2^−/−) mice or CD4⁺ T cell-specific Drd2-knockout (Drd2^fl/fl/CD4^Cre) mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD with the different mutants. On the 7th day following MPTP injection, mice were assessed for dopaminergic neurodegeneration, locomotor impairments, microglial activation, as well as CD4⁺ T-cell differentiation and function. Furthermore, in vitro CD4⁺ T cells were exposed to DRD2 agonist and antagonist and then differentiation and function of the cells were determined. MPTP induced dopaminergic neuronal loss in the nigrostriatal system, motor coordinative and behavioral impairments, microglial activation, and CD4⁺ T-cell polarization to pro-inflammatory T-helper (Th)1 and Th17 phenotypes. Importantly, either Drd2^−/− or Drd2^fl/fl/CD4^Cre mice manifested more severe dopaminergic neurodegeneration, motor deficits, microglial activation, and CD4⁺ T-cell bias towards Th1 and Th17 phenotypes in response to MPTP, but Drd1^−/− did not further alter MPTP intoxication. DRD2 agonist sumanirole inhibited shift of CD4⁺ T cells obtained from MPTP-intoxicated mice to Th1 and Th17 phenotypes and DRD2 antagonist L-741,626 reversed sumanirole effects. These findings suggest that DRD2 expressed on CD4⁺ T cells is protective against neuroinflammation and neurodegeneration in PD. Thus, developing a therapeutic strategy of stimulating DRD2 may be promising for mitigation of PD.     

Origins of a repetitive and co-contractive biphasic pattern of muscle activation in Parkinson’s disease

In studies of electromyographic (EMG) patterns during movements in Parkinson’s disease, often a repetitive and sometimes co-contractive pattern of antagonist muscle activation is observed. It has been suggested that the origin of such patterns of muscle activation is a central one arising from impairments in the basal ganglia structures and/or the cortex, although afferent inputs can also modulate the voluntary activity. A neural network model of Parkinson’s disease, bradykinesia and rigidity, is extended to quantitatively study the conditions under which such a repetitive and co-contractive pattern of muscle activation appears. Computer simulations show that an oscillatory disrupted globus pallidus internal segment (GPi) response signal comprising at least two excitation-inhibition sequences as an input to a normally functioning cortico-spinal model of movement generation results in a repetitive, but not co-contractive agonist-antagonist pattern of muscle activation. A repetitive and co-contractive pattern of muscle activation results when also dopamine is depleted in the cortex. Finally, additional dopamine depletion in the spinal cord sites results in a reduction of the size, duration and rate of change of the repetitive and co-contractive EMG bursts. These results have important consequences in the development of Parkinson’s Disease therapies such as dopamine replacement in cortex and spinal cord, which can alleviate some of the impairments of Parkinson’s Disease such as slowness of movement (bradykinesia) and rigidity.     

Effects of endogenous and exogenous D1/D5 dopamine receptor activation on LTP in ventral and dorsal CA1 hippocampal synapses

Hippocampus is importantly involved in dopamine‐dependent behaviors and dopamine is a significant modulator of synaptic plasticity in the hippocampus. Moreover, the dopaminergic innervation appears to be disproportionally segregated along the hippocampal longitudinal (dorsoventral) axis with unknown consequences for synaptic plasticity. In this study we examined the actions of endogenously released dopamine and the effects of exogenous D1/D5 dopamine receptor agonists on theta‐burst stimulation‐induced long‐term potentiation (LTP) of field excitatory synaptic potential (fEPSP) at Schaffer collateral‐CA1 synapses in slices from dorsal (DH) and ventral hippocampus (VH). Furthermore, we quantified D1 receptor mRNA and protein expression levels in DH and VH. We found that blockade of D1/D5 receptors by SCH 23390 (20 μM) significantly reduced the magnitude of LTP in both DH and VH similarly suggesting that dopamine endogenously released during TBS, presumably mimicking low activity of DA neurons, exerts a homogeneous modulation of LTP along the hippocampal long axis. Moderate to high concentrations of the selective partial D1/D5 receptor agonist SKF 38393 (50‐150 μM) did not significantly change LTP in either hippocampal segment. However, the full D1 receptor selective agonist SKF 82958 (10 μM) significantly enhanced LTP in VH but not DH. Furthermore, the expression of D1 receptor mRNA and protein was considerably higher in VH compared with DH. These results suggest that the dynamic range of D1/D5 receptor‐mediated dopamine effects on LTP may be higher in VH than DH and that VH may be specialized to acquire information about behaviorally relevant strong stimuli signaled by the dopamine system.     

Intracellularly recorded response of rat striatal neurons in vitro to fenoldopam and SKF 38393 following lesions of midbrain dopamine cells

The effect of long-term (6–19 weeks) 6-hydroxydopamine-induced (6-OHDA) lesions of midbrain dopamine cells on dopamine D₁-like agonist-induced changes in the excitability of rat striatal neurons was investigated in vitro using tissue slices and intracellular recording techniques. Fenoldopam and (±)-SKF 38393 predominantly decreased excitability in control preparations including striatal neurons located contralateral to 6-OHDA injection sites and neurons obtained from rats receiving sham injections or no treatment. Fenoldopam also inhibited neurons ipsilateral to lesions of midbrain dopamine cells. (±)-SKF 33393, unlike fenoldopam, produced predominantly increases in the excitability of ipsilateral striatal neurons. Superfusion of the D₁ receptor antagonist, SCH 23390, blocked fenoldopam-induced decreases in excitability but not the (±)-SKF 38393-induced excitation of neurons ipsilateral to the lesion. Sequential application of fenoldopam and quinpirole, a D₂/D₃ receptor agonist, produced responses to both drugs in a majority of neurons. The results demonstrate that inhibitory responses to fenoldopam are mediated by D₁ receptors, while excitatory effects of (±)-SKF 38393 in the striatum ipsilateral to the lesion are apparently not dependent on D₁ receptor activation. These findings also suggest that dopamine D₁ and D2/D3 receptors are able to concurrently influence the excitability of striatal neurons in the dopamine deafferentated striatum. Similar regulation of striatal neurons in vivo may contribute to dopaminergic regulation of basal ganglia output and the ability of dopaminomimetic agents to ameliorate symptoms of dopaminergic deficiency in Parkinson's disease. © 1994 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Delayed amyloid plaque deposition and behavioral deficits in outcrossed AβPP/PS1 mice

Alzheimer's disease (AD) is a progressive neurodegenerative dementia characterized by amyloid plaque accumulation, synapse/dendrite loss, and cognitive impairment. Transgenic mice expressing mutant forms of amyloid‐β precursor protein (AβPP) and presenilin‐1 (PS1) recapitulate several aspects of this disease and provide a useful model system for studying elements of AD progression. AβPP/PS1 mice have been previously shown to exhibit behavioral deficits and amyloid plaque deposition between 4–9 months of age. We crossed AβPP/PS1 animals with mice of a mixed genetic background (C57BL/6 × 129/SvJ) and investigated the development of AD‐like features in the resulting outcrossed mice. The onset of memory‐based behavioral impairment is delayed considerably in outcrossed AβPP/PS1 mice relative to inbred mice on a C57BL/6 background. While inbred AβPP/PS1 mice develop deficits in radial‐arm water maze performance and novel object recognition as early as 8 months, outcrossed AβPP/PS1 mice do not display defects until 18 months. Within the forebrain, we find that inbred AβPP/PS1 mice have significantly higher amyloid plaque burden at 12 months than outcrossed AβPP/PS1 mice of the same age. Surprisingly, inbred AβPP/PS1 mice at 8 months have low plaque burden, suggesting that plaque burden alone cannot explain the accompanying behavioral deficits. Analysis of AβPP processing revealed that elevated levels of soluble Aβ correlate with the degree of behavioral impairment in both strains. Taken together, these findings suggest that animal behavior, amyloid plaque deposition, and AβPP processing are sensitive to genetic differences between mouse strains. J. Comp. Neurol., 521:1395–1408, 2013. © 2012 Wiley Periodicals, Inc.     

Ultrastructural localization and function of dopamine D1‐like receptors in the substantia nigra pars reticulata and the internal segment of the globus pallidus of parkinsonian monkeys

The motor symptoms of Parkinson’s disease (PD) are commonly attributed to striatal dopamine loss, but reduced dopamine innervation of basal ganglia output nuclei, the internal globus pallidus (GPi) and the substantia nigra pars reticulata (SNr) may also contribute to symptoms and signs of PD. Both structures express dopamine D1 and D5 receptors under normal conditions, and we have recently demonstrated that their local activation reduces neuronal discharge rates and enhances bursts and oscillatory activity in both nuclei of normal monkeys [M.A. Kliem et al. (2007) J. Neurophysiol., 89, 1489–1500]. Here, we determined the ultrastructural localization and function of D1‐like receptors in 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP)‐treated parkinsonian monkeys. In both normal and MPTP‐treated monkeys, most of the D1 and D5 receptor immunoreactivity was associated with unmyelinated axons, but we also found significant postsynaptic D5 receptor immunostaining in dendrites of GPi and SNr neurons. A significant proportion of axonal D1 immunostaining was bound to the plasma membrane in both normal and MPTP‐treated monkeys. Local microinjections of the D1/D5 receptor agonist SKF82958 significantly reduced discharge rates in GPi and SNr neurons, while they increased burst firing and oscillatory activity in the 3–15‐Hz band in SNr, but not in GPi, of parkinsonian monkeys. Together with our recent findings from normal monkeys, these data provide evidence that functional D1/D5 receptors are expressed in GPi and SNr in both normal and parkinsonian states, and that their activation by endogenous dopamine (under normal conditions) or dopamine receptor agonists (in parkinsonism) may regulate basal ganglia outflow.     

Computational cognitive models of prefrontal-striatal-hippocampal interactions in Parkinson’s disease and schizophrenia

Disruption to different components of the prefrontal cortex, basal ganglia, and hippocampal circuits leads to various psychiatric and neurological disorders including Parkinson’s disease (PD) and schizophrenia. Medications used to treat these disorders (such as levodopa, dopamine agonists, antipsychotics, among others) affect the prefrontal-striatal-hippocampal circuits in a complex fashion. We have built models of prefrontal-striatal and striatal-hippocampal interactions which simulate cognitive dysfunction in PD and schizophrenia. In these models, we argue that the basal ganglia is key for stimulus-response learning, the hippocampus for stimulus-stimulus representational learning, and the prefrontal cortex for stimulus selection during learning about multidimensional stimuli. In our models, PD is associated with reduced dopamine levels in the basal ganglia and prefrontal cortex. In contrast, the cognitive deficits in schizophrenia are associated primarily with hippocampal dysfunction, while the occurrence of negative symptoms is associated with frontostriatal deficits in a subset of patients. In this paper, we review our past models and provide new simulation results for both PD and schizophrenia. We also describe an extended model that includes simulation of the different functional role of D1 and D2 dopamine receptors in the basal ganglia and prefrontal cortex, a dissociation we argue is essential for understanding the non-uniform effects of levodopa, dopamine agonists, and antipsychotics on cognition. Motivated by clinical and physiological data, we discuss model limitations and challenges to be addressed in future models of these brain disorders.     

Overexpression of human α-synuclein causes dopamine neuron death in rat primary culture and immortalized mesencephalon-derived cells

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the appearance of intracytoplasmic inclusions called Lewy bodies (LB) in dopamine neurons in the substantia nigra and the progressive loss of these neurons. Recently, mutations in the α-synuclein gene have been identified in early-onset familial PD, and α-synuclein has been shown to be a major component of LB in all patients. Yet, the pathophysiological function of α-synuclein remains unknown. In this report, we have investigated the toxic effects of adenovirus-mediated α-synuclein overexpression on dopamine neurons in rat primary mesencephalic cultures and in a rat dopaminergic cell line – the large T-antigen immortalized, mesencephalon-derived 1RB3AN27 (N27). Adenovirus-transduced cultures showed high-level expression of α-synuclein within the cells. Overexpression of human mutant α-synuclein (Ala₅₃Thr) selectively induced apoptotic programmed cell death of primary dopamine neurons as well as N27 cells. The mutant protein also potentiated the neurotoxicity of 6-hydroxydopamine (6-OHDA). By contrast, overexpression of wild-type human α-synuclein was not directly neurotoxic but did increase cell death after 6-OHDA. Overexpression of wild-type rat α-synuclein had no effect on dopamine cell survival or 6-OHDA neurotoxicity. These results indicate that overexpression of human mutant α-synuclein directly leads to dopamine neuron death, and overexpression of either human mutant or human wild-type α-synuclein renders dopamine neurons more vulnerable to neurotoxic insults.     

The Association of Blood-Based Inflammatory Factors IL-1β, TGF-β and CRP with Cognitive Function in Alzheimer’s Disease and Mild Cognitive Impairment

Objective Many patients suffer from dementia in its most common form, Alzheimer’s disease (AD). In this study, the levels of IL-1β, TGF-β and CRP, which are involved in the inflammatory response in Alzheimer’s disease and its mild cognitive impairment (MCI), were measured and analyzed. Methods Seventy nine subjects participated in this study (mean age: 75.56 years, female: 54.3%, AD: 26, MCI: 28, normal: 25). The overall cognitive function of the subjects and the severity of the disease stage were assessed using the Mini-Mental State Examination (MMSE-K), the Clinical Dementia Rating (CDR), the Global Deterioration Scale (GDS) and the Geriatric Depression Scale-Korean (GDS-K). Results It was observed that patients with AD had significantly higher levels of IL-1β and TGF-β than the patients with MCI and normal controls. In addition, the MCI group showed a statistically significantly higher TGF-β concentration than the normal group. Conclusion These results suggest that IL-1β and TGF-β may be useful biological markers for patients with Alzheimer’s disease.