Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

beta-Amyloid (1-40) and (25-35) have been reported to be toxic to primary cultured neurons. beta-Amyloid (1-40) was also reported to induce neurodegeneration following intracerebral injection. We attempted to replicate and extend these findings by injecting both the full length amyloid peptide and the 25-35 fragment. beta 1-40 (3 nmol in 1 microliter) or beta 25-35 (20 nmol in 2 microliters) in a vehicle of 10% DMSO (3 and 10 mM concentration, respectively) induced tissue loss and neurodegeneration. We also attempted to prevent the amyloid-induced damage by coinjecting 200 nmol of Substance P. There was no obvious reduction in the size of the lesions. Other studies, however, have reported antagonism of amyloid toxicity with tachykinin agonists. Since beta-amyloid does not appear to bind to tachykinin receptors, there is some question as to the site of the putative interaction of these peptides and, therefore, the mechanism by which beta-amyloid induces tissue damage. Our own results and published cell culture toxicity studies suggest that aggregation of the peptide and physical displacement of tissue may be responsible for both the neuronal and tissue loss, although this hypothesis is not consistent with other published findings.
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PMID:Intracerebral beta-amyloid(25-35) produces tissue damage: is it neurotoxic? 128 Dec 89

The salient pathological feature of Alzheimer disease (AD) is the presence of a high density of amyloid plaques in the brain tissue of victims. The plaques are predominantly composed of human beta-amyloid peptide (beta A4), a 40-mer whose neurotoxicity is related to its aggregation. Radioiodinated human beta A4 is rapidly deposited in vitro from a dilute (less than 10 pM) solution onto neuritic and diffuse plaques and cerebrovascular amyloid in AD brain tissue, whereas no deposition is detectable in tissue without performed plaques. This growth of plaques by deposition of radiolabeled beta A4 to plaques is reversible, with a dissociation half-time of approximately 1 h. The fraction of grey matter occupied by plaques that bind radiolabeled beta A4 in vitro is dramatically larger in AD cortex (23 +/- 11%) than in age-matched normal controls (less than 2%). In contrast to the human peptide, rat/mouse beta A4 (differing at three positions from human beta A4) does not affect the deposition of radiolabeled human beta A4. beta A4 has no detectable interaction with tachykinin receptors in rat or human brain. The use of radioiodinated beta A4 provides an in vitro system for the quantitative evaluation of agents or conditions that may inhibit or enhance the growth or dissolution of AD plaques. This reagent also provides an extremely sensitive method for visualizing various types of amyloid deposits and a means for characterizing and locating sites of amyloid peptide binding to cells and tissues.
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PMID:Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide. 160 56

The distribution of chromogranin A (CgA), a soluble protein in dense-core synaptic vesicles expressed by a variety of neuronal cell types, was studied immunocytochemically in Alzheimer's disease and normal aging. In addition to its presence in neuronal perikarya and process, CgA-like immunoreactivity (CgA-li) was demonstrated in multiple dystrophic neurites forming the crown of senile plaques. Two different monoclonal antibodies, LK2H10 and PHE5, gave identical results. In the two regions of the brain studied--the calcarine cortex and the molecular layer of the dentate gyrus--the areal density of plaques associated with CgA-like immunoreactive neurites was greater than the density of Congo red-stainable amyloid cores, but smaller than the density of beta amyloid peptide deposits identified by the Campbell silver stain. By comparison, other synaptically released peptides--somatostatin 28, somatostatin 14, substance P, cholecystokinin, neurotensin, vasoactive intestinal peptide, and leu-enkephalin--were immunocytochemically detected in less than 30% of plaques. Thus CgA appears unique among known synaptically released substances in being present in dystrophic neurites in virtually all classic (i.e., Congo red stainable) plaques and additionally in a subpopulation of preamyloid plaques.
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PMID:Chromogranin A-like immunoreactive neurites are major constituents of senile plaques. 171 Jul 35

Deposition of the beta-amyloid protein in senile plaques is a pathologic hallmark of Alzheimer disease (AD). Focal deposition of beta amyloid in the adult rat cerebral cortex caused profound neurodegenerative changes, including neuronal loss and degenerating neurons and neurites. Chronic induction of the Alz-50 antigen appeared in neurons around focal cortical deposits of beta amyloid. Immunoblot analysis showed that beta amyloid induced Alz-50-immunoreactive proteins in rat cerebral cortex that were very similar to the proteins induced in human cerebral cortex from patients with AD. The neuropeptide substance P prevented beta-amyloid-induced neuronal loss and expression of Alz-50 proteins when coadministered into the cerebral cortex. Systemic administration of substance P also provided protection against the effects of intracerebral beta amyloid. Thus, beta amyloid is a potent neurotoxin in the adult brain in vivo, and its effects can be blocked by substance P.
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PMID:An in vivo model for the neurodegenerative effects of beta amyloid and protection by substance P. 171 96

Double immunofluorescence studies using antibodies against NF-L and peripherin revealed three distinct subpopulations of neurons in rat dorsal root ganglia (DRG). In the adult rat, 46% of the DRG neurons were small and peripherin-positive (NF-L-negative), and 48% were large and NF-L-positive (peripherin-negative). About 6% were both peripherin- and NF-L-positive. All of the DRG neurons reacted with antibodies to NF-M and nonphosphorylation-dependent or phosphorylation-independent antibodies to NF-H. The neuropeptides were predominantly found in the peripherin-positive small cell population. Eighty-seven percent of the peripherin-positive small cell population contained substance P immunoreactivity, while 43% of this cell population contained CGRP. In contrast, only 18-24% of the NF-L-positive large-cell population contained neuropeptides, and these were primarily in a smaller sized subpopulation. Similar patterns of antigen representation were observed in neonatal (PN2) DRG cell populations. Tissue cultures of sensory ganglion cells from PN2 DRG, in serum-free medium, stably maintained exclusively peripherin-positive neurons, with about 5% of these containing coexistent NF-L immunoreactivity. Very high levels of neuropeptide gene expression were exhibited by these postnatal neurons in culture.
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PMID:NF-L and peripherin immunoreactivities define distinct classes of rat sensory ganglion cells. 179 10

Degeneration of cholinergic neurons from the basal forebrain nuclei is suspected to be the cause of Alzheimer disease. We have developed dissociated cultures of cholinergic neurons from these nuclei (the nucleus basalis of Meynert, the medial septal nucleus, and the diagonal band nuclei). Brain slices of the forebrains were made by a vibratome, and the basal forebrain nuclei were dissected out, dissociated, and cultured. Choline acetyltransferase immunocytochemistry and acetylcholinesterase cytochemistry revealed large cholinergic cells (average diameter, 20-25 micron) in these cultures. About 75% of large neurons (20 micron or larger in diameter) were cholinergic. Electrophysiological experiments were performed on these large neurons. The neurons usually did not show spontaneous firing, but steady depolarizations produced trains of action potentials, which adapted quickly. The neurons responded with depolarization to the application of L-glutamic acid. Substance P produced depolarization (sometimes hyperpolarization), and during the depolarization membrane resistance was increased.
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PMID:Dissociated cell culture of cholinergic neurons from nucleus basalis of Meynert and other basal forebrain nuclei. 241 32

The concentration of substance P-like immunoreactive material (SPLI) and somatostatin-like immunoreactive material (SLI) and the activity of acetyl-CoA: choline-O-acetyltransferase (ChAT; EC 2.3.1.6) were measured in eight brain regions of 13 normal patients and 12 patients with Alzheimer disease/senile dementia of the Alzheimer type (AD/SDAT). SPLI was significantly lower in five of eight regions in the patients with AD/SDAT. Younger patients with AD/SDAT had significantly lower SLI in the parietal cortex than older patients. ChAT activity and SPLI in the parietal cortex of the presenile patients with AD/SDAT were not significantly different from values found in older patients.
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PMID:Cortical substance P-like immunoreactivity in cases of Alzheimer's disease and senile dementia of the Alzheimer type. 617 86

Neurodegenerative processes in Alzheimer disease (AD) are thought to be driven in part by the deposition of amyloid beta (A beta), a 39- to 43-amino acid peptide product resulting from an alternative cleavage of amyloid precursor protein. Recent descriptions of in vitro neurotoxic effects of A beta support this hypothesis and suggest toxicity might be mediated by A beta-induced neuronal calcium disregulation. In addition, it has been reported that "aging" A beta results in increased toxic potency due to peptide aggregation and formation of a beta-sheet secondary structure. In addition, A beta might also promote neuropathology indirectly by activating immune/inflammatory pathways in affected areas of the brain (e.g., cortex and hippocampus). Here we report that A beta can modulate cytokine secretion [interleukins 6 and 8 (IL-6 and IL-8)] from human astrocytoma cells (U-373 MG). Freshly prepared and aged A beta modestly stimulated IL-6 and IL-8 secretion from U-373 MG cells. However, in the presence of interleukin-1 beta (IL-1 beta), aged, but not fresh, A beta markedly potentiated (3- to 8-fold) cytokine release. In contrast, aged A beta did not potentiate substance P (NK-1)- or histamine (H1)-stimulated cytokine production. Further studies showed that IL-1 beta-induced cytokine release was potentiated by A beta-(25-35), while A beta-(1-16) was inactive. Calcium disregulation may be responsible for the effects of A beta on cytokine production, since the calcium ionophore A23187 similarly potentiated IL-1 beta-induced cytokine secretion and EGTA treatment blocked either A beta or A23187 activity. Thus, chronic neurodegeneration in AD-affected brain regions may be mediated in part by the ability of A beta to exacerbate inflammatory pathways in a conformation-dependent manner.
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PMID:Amyloid beta peptide potentiates cytokine secretion by interleukin-1 beta-activated human astrocytoma cells. 747 75

A synthetic truncated beta-amyloid peptide, beta 22-35, was shown to have a cytotoxic effect on cultured neurons from the rat hippocampus in serum-free medium. The peptide formed aggregates and typical amyloid fibrils resembling those of the beta-amyloid protein (AP) in neutral buffer solution and showed characteristic staining with Congo red and thioflavin-S. The neurotoxicity of beta 22-35 was suppressed by addition of calf serum, dibutyryl cAMP or insulin to culture medium, but not by addition of NGF or substance P. beta 22-35 had no effect on the glial cells. These results suggest that the AP can induce neurotoxicity in the hippocampal cells in vitro and the toxicity may involve a disorder in the intracellular signal transduction.
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PMID:Toxic effect of a beta-amyloid peptide (beta 22-35) on the hippocampal neuron and its prevention. 750 1

Microglia (brain resident macrophages) have been found to be closely associated with beta amyloid containing plaques in brain tissue affected by Alzheimer disease (AD). To investigate whether beta amyloid peptide (beta AP) may activate microglia, the effects of synthetic beta AP (amino acids 1-40) and a subfragment (amino acids 25-35) on rat peritoneal macrophages were assessed using four different assays for activation. These peptides were compared with substance P, which has previously been shown to activate macrophages. Both beta amyloid peptides activated macrophages, as assessed by increased respiratory burst-associated oxygen consumption, by luminol-dependent chemiluminescence, and by aggregation. In addition, beta amyloid peptide (1-40) caused a significant increase in macrophage nitric oxide production, while subfragment (25-35) did not. Substance P caused significant activation as assessed by oxygen consumption and chemiluminescence, but not by aggregation or nitric oxide induction.
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PMID:Activation of macrophages by Alzheimer beta amyloid peptide. 751 Sep 64


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