Treadmill exercise delays the onset of non-motor behaviors and striatal pathology in the CAG140 knock-in mouse model of Huntington's disease.

Depression, cognitive impairments, and other neuropsychiatric disturbances are common during the prodromal phase of Huntington's disease (HD) well before the onset of classical motor symptoms of this degenerative disorder. The purpose of this study was to examine the potential impact of physical activity in the form of exercise on a motorized treadmill on non-motor behavioral features including depression-like behavior and cognition in the CAG140 knock-in (KI) mouse model of HD. The CAG140 KI mouse model has a long lifespan compared to other HD rodent models with HD motor deficits emerging after 12months of age and thus provides the opportunity to investigate early life interventions such as exercise on disease progression. Motorized treadmill running was initiated at 4weeks of age (1h per session, 3 times per week) and continued for 6months. Non-motor behaviors were assessed up to 6months of age and included analysis of depression-like behavior (using the tail-suspension and forced-swim tests) and cognition (using the T-maze and object recognition tests). At both 4 and 6months of age, CAG140 KI mice displayed significant depression-like behavior in the forced swim and tail suspension tests and cognitive impairment by deficits in reversal relearning in the T-maze test. These deficits were not evident in mice engaged in treadmill running. In addition, exercise restored striatal dopamine D2 receptor expression and dopamine neurotransmitter levels both reduced in sedentary HD mice. Finally, we examined the pattern of striatal expression of mutant huntingtin (mHTT) protein and showed that the number and intensity of immunohistochemical staining patterns of intranuclear aggregates were significantly reduced with exercise. Altogether these findings begin to address the potential impact of lifestyle and early intervention such as exercise on modifying HD progression.

Exercise modifies α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor expression in striatopallidal neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse.

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic-acid-type glutamate receptor (AMPAR) plays a critical role in modulating experience-dependent neuroplasticity, and alterations in AMPAR expression may underlie synaptic dysfunction and disease pathophysiology. Using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of dopamine (DA) depletion, our previous work showed exercise increases total GluA2 subunit expression and the contribution of GluA2-containing channels in MPTP mice. The purpose of this study was to determine whether exercise-dependent changes in AMPAR expression after MPTP are specific to the striatopallidal (D2 R) or striatonigral (D1 R) medium spiny neuron (MSN) striatal projection pathways. Drd2 -eGFP-BAC transgenic mice were used to delineate differences in AMPAR expression between striatal D2 R-MSNs and D1 R-MSNs. Striatal AMPAR expression was assessed by immunohistochemical (IHC) staining, Western immunoblotting (WB) of preparations enriched for postsynaptic density (PSD), and alterations in the current-voltage relationship of MSNs. We found DA depletion results in the emergence of GluA2-lacking AMPARs selectively in striatopallidal D2 R-MSNs and that exercise reverses this effect in MPTP mice. Exercise-induced changes in AMPAR channels observed after DA depletion were associated with alterations in GluA1 and GluA2 subunit expression in postsynaptic protein, D2 R-MSN cell surface expression, and restoration of corticostriatal plasticity. Mechanisms regulating experience-dependent changes in AMPAR expression may provide innovative therapeutic targets to increase the efficacy of treatments for basal ganglia disorders, including Parkinson's disease.

The Effects of Exercise on Dopamine Neurotransmission in Parkinson's Disease: Targeting Neuroplasticity to Modulate Basal Ganglia Circuitry.

Animal studies have been instrumental in providing evidence for exercise-induced neuroplasticity of corticostriatal circuits that are profoundly affected in Parkinson's disease. Exercise has been implicated in modulating dopamine and glutamate neurotransmission, altering synaptogenesis, and increasing cerebral blood flow. In addition, recent evidence supports that the type of exercise may have regional effects on brain circuitry, with skilled exercise differentially affecting frontal-striatal related circuits to a greater degree than pure aerobic exercise. Neuroplasticity in models of dopamine depletion will be reviewed with a focus on the influence of exercise on the dorsal lateral striatum and prefrontal related circuitry underlying motor and cognitive impairment in PD. Although clearly more research is needed to address major gaps in our knowledge, we hypothesize that the potential effects of exercise on inducing neuroplasticity in a circuit specific manner may occur through synergistic mechanisms that include the coupling of an increasing neuronal metabolic demand and increased blood flow. Elucidation of these mechanisms may provide important new targets for facilitating brain repair and modifying the course of disease in PD.

Combined assessment of tau and neuronal thread protein in Alzheimer's disease CSF.

OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.

The native form of alpha-synuclein is not found in the cerebrospinal fluid of patients with Parkinson's disease or normal controls.

Alpha-synuclein has recently been shown to be a major constituent of Lewy bodies in Parkinson's disease (PD). This observation led us to investigate the possibility that its detection in the cerebrospinal fluid (CSF) could be used as a marker for Lewy bodies in the central nervous system. In this study we determined the pattern of expression of alpha-synuclein in patients with sporadic Parkinson's disease (PD) and normal controls, using western immunoblotting in conjunction with an antibody that recognizes the carboxyl terminal of alpha-synuclein protein. The native 19 kDa band normally seen in brain homogenates was not found in the CSF of either parkinsonian patients or control subjects. However, a novel band was observed, which migrated at a position in the range of 42 kDa in CSF from both patients and controls. We conclude that alpha-synuclein cannot be used as a biomarker for Lewy bodies during life. However, further characterization of the 42 kDa protein may be of interest.

Postnatal expression of alpha-synuclein protein in the rodent substantia nigra and striatum.

A primary goal of our research is to elucidate the mechanisms involved in neuroplasticity of the basal ganglia in both development and in response to injury. One means to this aim is through the analysis of the ontological profile of proteins in the basal ganglia and to correlate their pattern of expression with morphological development. One protein thought to be important in neuroplasticity is alpha-synuclein. The purpose of this study was to characterize and compare the pattern of expression of alpha-synuclein protein using immunocytochemistry in the substantia nigra and striatum of the rodent in early postnatal and adult life. Our results demonstrate that there is a high level of expression of alpha-synuclein protein within cell bodies of the substantia nigra pars compacta in the 1st week of postnatal life that decreases both in intensity and number of immunoreactive cells between postnatal days 7 and 14. This is in contrast to the substantia nigra pars reticulata where alpha-synuclein protein expression in the neuropil increases after postnatal day 7. In the striatum, expression in early postnatal life is distributed in a mosaic-like fashion and becomes more diffuse after postnatal day 14. Our results support the findings of others that expression of alpha-synuclein is developmentally regulated and suggest that alpha-synuclein may play an important role in establishing the function of the basal ganglia. Understanding the role of alpha-synuclein in the normal basal ganglia may provide insights into the molecular mechanisms involved in neuroplasticity in response to injury.

Experimental models of Parkinson's disease: insights from many models.

Toxin-induced and genetic experimental models have been invaluable in investigating idiopathic Parkinson's disease (PD). The neurotoxins--reserpine, 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and methamphetamine--have been used to develop parkinsonian models in a wide variety of species. Both 6-OHDA and MPTP can replicate the neurochemical, morphologic, and behavioral changes seen in human disease. The unilateral 6-OHDA rat model is an excellent model for testing and determining modes of action of new pharmacologic compounds. The nonhuman primate MPTP-induced parkinsonian model has behavioral features that best approximate idiopathic PD. These induced and genetic models have been used to study the pathophysiology of the degenerating nigrostriatal system and to evaluate novel therapeutic strategies. Important differences within these models provide insights into various aspects of the dopaminergic phenotype and its role as a target in disease. These models provide an avenue to evaluate many anti-parkinsonian compounds, such as levodopa, which was first evaluated in an animal model and is the gold standard of parkinsonian treatment today.

Reliability and validity of a new global dyskinesia rating scale in the MPTP-lesioned non-human primate.

Behavioral rating scales for dyskinesia in the non-human primate are frequently used to assess the efficacy of new treatments and to provide a clinical correlative with neurochemical and neuropathological changes. Although a large variety of different scales have been used in non-human primate studies, there is no single standardized scale, and none have been evaluated for reliability and validity. We are reporting a new global non-human primate dyskinesia rating scale (GPDRS) for the squirrel monkey, developed in the context of an independent study of dyskinesia. In this report we demonstrate the reliability and validity of this scale. The GPDRS is a single-item scale with well-defined points and brevity allowing for rapid and easy application for assessing the overall degree of dyskinesia. In this study, seven MPTP-lesioned and four non-lesioned (control) non-human primates were videotaped following treatment with either levodopa or water. To test inter- and intra-rater reliability, three examiners rated the videotape independently at two different time points and these assessments were compared. The validity of the scale was tested in two phases. First, examiners rated the videotape using the GPDRS and the Abnormal Involuntary Movement Scale (AIMS), a scale commonly used to rate dyskinesia in the non-human primate, and the ratings from each scale were compared. Second, validity was tested in the context of an independent dyskinesia study, in which the scale was used to distinguish between two treatment groups. The GPDRS was shown to have high inter- and intra-rater reliability and to be valid for the assessment of dyskinesia in the squirrel monkey. In this report we also demonstrate the inter- and intra-rater reliability of the AIMS.