Loss of basal forebrain P75(NTR) immunoreactivity in subjects with mild cognitive impairment and Alzheimer's disease.

The long-held belief that degeneration of the cholinergic basal forebrain was central to Alzheimer's disease (AD) pathogenesis and occurred early in the disease process has been questioned recently. In this regard, changes in some cholinergic basal forebrain (CBF) markers (e.g.

Down-regulation of trkA mRNA within nucleus basalis neurons in individuals with mild cognitive impairment and Alzheimer's disease.

Recent studies indicate that trkA expression is reduced in end-stage Alzheimer's disease (AD). However, understanding the neuropathologic correlates of early cognitive decline, as well as the changes that underlie the transition from nondemented mild cognitive impairment (MCI) to AD, are more critical neurobiological challenges. In these regards, the present study examined the expression of trkA mRNA in individuals diagnosed with MCI and AD from a cohort of people enrolled in a Religious Orders Study.

Early degenerative changes in transgenic mice expressing mutant huntingtin involve dendritic abnormalities but no impairment of mitochondrial energy production.

Mitochondrial defects, which occur in the brain of late-stage Huntington's disease (HD) patients, have been proposed to underlie the selective neuronal loss in the disease. To shed light on the possible role of mitochondrial energy impairment in the early phases of HD pathophysiology, we carried out Golgi impregnation and quantitative histochemical/biochemical studies in HD full-length cDNA transgenic mice that were symptomatic but had not developed to a stage in which neuronal loss could be documented. Golgi staining showed morphologic abnormalities that included a significant decrease in the number of dendritic spines and a thickening of proximal dendrites in striatal and cortical neurons.

Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment.

Layer II of the entorhinal cortex contains the cells of origin for the perforant path, plays a critical role in memory processing, and consistently degenerates in end-stage Alzheimer's disease. The extent to which neuron loss in layer II of entorhinal cortex is related to mild cognitive impairment without dementia has not been extensively investigated. We analyzed 29 participants who came to autopsy from our ongoing longitudinal study of aging and dementia composed of religious clergy (Religious Orders Study).

Ontogeny of the dopamine D2 receptor mRNA expressing cells in the human hippocampal formation and temporal neocortex.

The study details the cellular expression of the dopamine D2 receptor mRNA in the human temporal lobe during prenatal development. At 13 embryonic weeks (E13) D2 mRNA was widely expressed in the temporal lobe. At this time point in the dentate gyrus D2 mRNA positive cells first appeared at the outer border of the granular layer and their number increased with development.

Systemic administration of the immunophilin ligand GPI 1046 in MPTP-treated monkeys.

Systemic administration of immunophilin ligands provides trophic influences to dopaminergic neurons in rodent models of Parkinson's disease (PD) resulting in the initiation of clinical trials in patients with Parkinson's disease. We believe that prior to clinical trials, novel therapeutic strategies should show safety and efficacy in nonhuman models of PD. The present study assessed whether oral administration of the immunophilin 3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrollidinecarboxylate (GPI 1046) could prevent the structural and functional consequences of n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in nonhuman primates.

Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology.

Neural and stem cell transplantation is emerging as a potential treatment for neurodegenerative diseases. Transplantation of specific committed neuroblasts (fetal neurons) to the adult brain provides such scientific exploration of these new potential therapies. Huntington's disease (HD) is a fatal, incurable autosomal dominant (CAG repeat expansion of huntingtin protein) neurodegenerative disorder with primary neuronal pathology within the caudate-putamen (striatum).

Neurodegeneration prevented by lentiviral vector delivery of GDNF in primate models of Parkinson's disease.

Lentiviral delivery of glial cell line-derived neurotrophic factor (lenti-GDNF) was tested for its trophic effects upon degenerating nigrostriatal neurons in nonhuman primate models of Parkinson's disease (PD). We injected lenti-GDNF into the striatum and substantia nigra of nonlesioned aged rhesus monkeys or young adult rhesus monkeys treated 1 week prior with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Extensive GDNF expression with anterograde and retrograde transport was seen in all animals.

Loss of nucleus basalis neurons containing trkA immunoreactivity in individuals with mild cognitive impairment and early Alzheimer's disease.

Recent studies indicate that there is a marked reduction in trkA-containing nucleus basalis neurons in end-stage Alzheimer's disease (AD). We used unbiased stereological counting procedures to determine whether these changes extend to individuals with mild cognitive impairment (MCI) without dementia from a cohort of people enrolled in the Religious Orders Study. Thirty people (average age 84.

B2 bradykinin receptor immunoreactivity in rat brain.

Bradykinin has long been known to exist in the central nervous system and has been hypothesized to mediate specific functions. Despite an increasing understanding of the functions of bradykinin, little is known about the cell types expressing the bradykinin receptor within the brain. The present investigation employed a monoclonal antibody directed against the 15-amino-acid portion of the C-terminal of the human bradykinin B2 receptor to establish the cellular distribution of bradykinin B2 receptor immunoreactivity in the rat brain.

Age-related decreases in GTP-cyclohydrolase-I immunoreactive neurons in the monkey and human substantia nigra.

Guanosine triphosphate cyclohydrolase I (GTPCHI) is a critical enzyme in catecholamine function and is rate limiting for the synthesis of the catecholamine co-factor tetrahydrobiopterin. The present study assessed the distribution of GTPCHI immunoreactivity (-ir) within the monkey and human ventral midbrain and determined whether its expression is altered as a function of age. Light and confocal microscopic analyses revealed that young monkeys and humans displayed GTPCHI-ir within melanin-containing and tyrosine-hydroxylase-ir neurons in primate substantia nigra.

Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity.

The neuroprotective properties of cyclosporin A (CsA) are mediated by its ability to prevent mitochondrial permeability transition during exposure to high levels of calcium or oxidative stress. By using the mitochondrial toxin 3-nitropropionic acid (3NP), the present study assessed whether CsA could protect striatal neurons in vitro and in vivo. In vitro, 3NP produced a 20-30% reduction of striatal glutamic acid decarboxylase-immunoreactive (GAD-ir) neurons.

Delayed onset of progressive dystonia following subacute 3-nitropropionic acid treatment in Cebus apella monkeys.

Delayed abnormal movements can be observed in patients with acute neurologic insult after a prolonged period of apparent neurologic stability. To reproduce such a secondary neurologic manifestation in primates, the present experiment investigated whether systemic administration of subacute 3-nitropropionic acid (3NP), a mitochondrial toxin, could induce abnormal movements that were delayed and progressive over time. Four Cebus apella monkeys received systemic 3NP injections until acute neurologic signs manifested.

Delayed onset of progressive dystonia following subacute 3-nitropropionic acid treatment in Cebus apella monkeys.

Delayed abnormal movements can be observed in patients with acute neurologic insult after a prolonged period of apparent neurologic stability. To reproduce such a secondary neurologic manifestation in primates, the present experiment investigated whether systemic administration of subacute 3-nitropropionic acid (3NP), a mitochondrial toxin, could induce abnormal movements that were delayed and progressive over time. Four Cebus apella monkeys received systemic 3NP injections until acute neurologic signs manifested.

Reduction in TrkA-immunoreactive neurons is not associated with an overexpression of galaninergic fibers within the nucleus basalis in Down's syndrome.

Down's syndrome (DS) individuals develop neuropathological features similar to Alzheimer's disease (AD), including degeneration of cholinergic basal forebrain (CBF) neurons. In AD a reduction in CBF/trkA-containing neurons has been suggested to trigger a hyperexpression of galaninergic fibers within the nucleus basalis subfield of the basal forebrain. The present study examined the interrelationship between reductions in CBF/trkA-containing neurons and the overexpression of galaninergic fibers within the nucleus basalis in DS.

Evidence that Cereport's ability to increase permeability of rat gliomas is dependent upon extent of tumor growth: implications for treating newly emerging tumor colonies.

Cereport (RMP-7) enhances delivery of chemotherapeutics into brain tumors by increasing the permeability of the glioma vasculature (i.e. , the blood-brain tumor barrier; BBTB).

Lentiviral gene transfer to the nonhuman primate brain.

Lentiviral vectors infect quiescent cells and allow for the delivery of genes to discrete brain regions. The present study assessed whether stable lentiviral gene transduction can be achieved in the monkey nigrostriatal system. Three young adult Rhesus monkeys received injections of a lentiviral vector encoding for the marker gene beta galatosidase (beta Gal).