Molecular and morphological correlates following neuronal deafferentation: a cortico-striatal model.
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Afferent Pathways↗
Biomedical subjects
G M Pasinetti
Publications and source records attributed to G M Pasinetti.
Disappearance of GAD-mRNA and tyrosine hydroxylase in substantia nigra following striatal ibotenic acid lesions: evidence for transneuronal regression.
Transneuronal regression in substantia nigra reticulata (SNR) and substantia nigra compacta (SNC) neurons was studied in Fischer 344 male rats by immunocytochemistry and by in situ hybridization. Three months after striatal lesioning by ibotenic acid, there was a shrinkage (30%) of the SNR region cross-sectional area and a 50% disappearance of neurons that contain glutamic acid decarboxylase (GAD)-mRNA, but only in the ventromedial portion of this nucleus. Loss of dopaminergic neurons, as recognized by tyrosine hydroxylase immunoreactivity, occurred only in caudal portions of the SNC and SNR. These findings suggest that lesions in reciprocally connected pathways, like the nigrostriatal and striatonigral systems, may produce a vicious cycle (feedforward cascade) of neurodegeneration due to interference with retrograde ana anterograde influences.
Animals↗
Tyrosine hydroxylase mRNA concentration in midbrain dopaminergic neurons is differentially regulated by reserpine.
Tyrosine hydroxylase (TH)-mRNA, assayed by in situ hybridization combined with TH immunocytochemistry, showed a selective increase in the ventral tegmental area (A-10) but not in the substantia nigra (A-9) midbrain dopaminergic (DAergic) neurons 3 days after reserpine treatment. TH-mRNA in locus ceruleus noradrenergic (A-4) neurons was increased by reserpine, as confirmed by RNA blot hybridization. These findings show that TH-mRNA is differentially regulated in midbrain DAergic neurons in response to reserpine.
Animals↗
Chronic lesions differentially decrease tyrosine hydroxylase messenger RNA in dopaminergic neurons of the substantia nigra.
Long-term effects of lesions were analyzed in terms of gene expression. Nine months after unilateral 6-hydroxydopamine (6-OHDA) lesions of the substantia nigra pars compacta (s. nigra), the remaining dopaminergic (DAergic) neurons (tyrosine hydroxylase (TH) cells determined by immunocytochemistry (ICC] on the lesioned side were atrophic with smaller nucleoli. By in situ hybridization, the DAergic neurons on the lesioned side had a 50% smaller TH-mRNA concentration than on the contralateral non-lesioned side. However, beta-tubulin mRNA concentration in DAergic neurons was unaffected by the lesion. The lesions did not alter TH-mRNA concentration in the contralateral non-lesioned side by comparison with unoperated controls. We propose that chronic lesions have long-term effects on gene expression because of damage sustained during compensatory hyperactivity after the lesion, or because of decreased trophic support from other neurons.
Animals↗
Selective reduction of mRNA for the beta-amyloid precursor protein that lacks a Kunitz-type protease inhibitor motif in cortex from Alzheimer brains.
In poly(A) RNA from cerebral cortex obtained postmortem from victims of Alzheimer's disease (AD), an alternatively spliced mRNA for the amyloid precursor protein (APP-695 mRNA) was shown to be decreased by 65%. Another form (APP-751 mRNA) with an additional exon encoding a Kunitz-type (serine) protease inhibitor motif did not change appreciably (less than 30% decrease) in AD cortex. If this twofold increase in the APP-751 mRNA/APP-695 mRNA ratio results in a corresponding increase in the APP-751/APP-695 protein ratio, this would support the hypothesis that impaired proteolysis promotes the accumulation of abnormal proteins in the brain during AD. In the two previously known, major alternatively spliced forms of ca. 3.3 and 3.5 kb, we resolved doublet RNAs for each form that are consistent with sequence data showing multiple polyadenylation sites (J. Kang et al., 1987, Nature (London) 325, 733-736.). Smaller APP-related transcripts were also found (1.1, 1.0, 0.8, and 0.3 kb), some of which are selectively altered in AD.
Alzheimer Disease↗
Complement mRNA in the mammalian brain: responses to Alzheimer's disease and experimental brain lesioning.
This study describes evidence in the adult human and rat brain for mRNAs that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA. In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.
Aged↗
Inflammatory mechanisms in neurodegeneration and Alzheimer's disease: the role of the complement system.
This review discusses key findings indicating potential roles of the complement (C)-system in chronic inflammation in Alzheimer's disease (AD) brain. Although there is no means to cure or prevent the disease, recent studies suggest that antiinflammatory drugs may delay the onset of AD dementia. One target of these drugs may be the (C)-system, which is best known for its roles in inflammatory processes in peripheral tissues. However, recent data show C-system expression and regulation in brain cells, and C-system protein deposition in AD plaques. It is still nuclear whether C-system activation contributes to neuropathology in the AD brain, as shown in multiple sclerosis (MS). New clinical studies with antiinflammatory agents are now under general consideration by the Alzheimer's Disease Cooperative Study program. In this review I outline research directions which address possible C-system contributions to neurodegeneration. Finally, I discuss potential pharmacological interventions designed to control segments of classical inflammatory cascades in which the C-system is highly implicated. These aspects are critical to the understanding of C-mediated responses in normal and pathologic brain.
Alzheimer Disease↗
Combined in situ hybridization and immunocytochemistry in the assay of pharmacological effects on tyrosine hydroxylase mRNA concentration.
An assay for tyrosine hydroxylase (TH) mRNA by in situ hybridization in combination with immunocytochemistry (ICC) for TH on the same section is described. The in situ hybridization protocol was optimized for [35S]cRNA (complementary RNA, i.e. anti-sense strand) probe concentration and time of hybridization. The specificity of hybridization was measured by several critera. The advantage of measuring grain density versus grains per cell is discussed for quantitation of in situ autoradiography. Finally, the reserpine-induced increase in adrenal TH mRNA was used to validate quantitative aspects of the in situ hybridization technique by comparison with blot hybridization. In contrast to the adrenal, reserpine did not increase TH mRNA in substantia nigra (s. nigra) neurons as measured by either technique.
Animals↗
Elevated plasma neopterin levels in Alzheimer disease.
We assessed plasma neopterin level as a marker of inflammation in Alzheimer disease (AD). Plasma neopterin levels were higher in 51 patients with AD (9.3 +/- 5.9 ng/mL) than in 38 age-matched control subjects (6.3 +/- 2.6 ng/ml, p = 0.002). There was no correlation between neopterin levels and Mini-Mental State Examination score or duration of disease; there was a weak association between neopterin level and age (r = 0.26, p = 0.02). Although measurement of plasma neopterin levels is not useful for diagnosis, this assay may provide guidance for the development of anti-inflammatory treatment strategies for AD.
Aged↗