volkensin and Alzheimer-Disease

Experimental lesions using the retrogradely transported toxin, volkensin, have been used in conjunction with autoradiography to investigate the cellular localization of 5-HT1A, muscarinic M1 and nicotinic receptors. Selective destruction of neocortical pyramidal neurones forming the corticostriatal or corticocortical pathways was achieved by intrastriatal or intracortical injection of volkensin. Selective destruction of layer V corticostriatal neurones was accompanied by loss of binding in the cortex to 5-HT1A and muscarinic M1 receptors, and an upregulation of [3H] nicotine binding contralateral to the pyramidal cell loss. Destruction of corticocortical neurones was accompanied by loss of binding to muscarinic and nicotinic receptors. The presence of these cholinoceptors on corticocortical neurones was confirmed by recording carbachol-induced depolarizations from a novel cortical brain slice preparation. It is proposed that cholinoceptors represent a consistent marker for neocortical pyramidal cells, and as such are viable targets for the continuing development of therapies designed to ameliorate the cortical hypoactivity observed in Alzheimer's disease. Ligands for these receptors may also be suitable for positron emission tomography to assess pyramidal neurone numbers in suspected Alzheimer's disease.

Topics: Alzheimer Disease; Autoradiography; Carbachol; Cerebral Cortex; Electrophysiology; Glycoproteins; Humans; In Vitro Techniques; Muscarinic Agonists; N-Glycosyl Hydrolases; Nicotinic Agonists; Plant Lectins; Plant Proteins; Pyramidal Cells; Receptors, Muscarinic; Receptors, Nicotinic; Ribosome Inactivating Proteins, Type 2

Concentrations of APP-like immunoreactivity have been determined by western blotting in a soluble fraction and two membrane fractions of brain cortex from demented patients (14 with Alzheimer's disease and 8 with other diagnoses). The concentration of APP in the soluble fraction correlated with the number of pyramidal neurones but not astrocytes or indices of interneurones. Experimental lesions in rats and quantitative autoradiography were used to investigate the cellular localisation of receptors. Lesions were produced by intrastriatal or intracortical injections of volkensin to destroy corticofugal and corticortical pyramidal neurons respectively. Volkensin treatment caused significant loss of pyramidal neurones which was accompanied by reduced binding to muscarinic cholinergic m1 receptors. [3H] 8-OH-DPAT (serotonin 1A receptors) binding was reduced only following intrastriatal volkensin. Results from the human and rat investigations are discussed in terms of the biology of cortical pyramidal neurones and drugs for the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Animals; Brain; Cerebral Cortex; Glycoproteins; Male; N-Glycosyl Hydrolases; Neurons; Plant Lectins; Plant Proteins; Rats; Rats, Wistar; Receptors, Adrenergic; Receptors, Biogenic Amine; Receptors, GABA-A; Receptors, Kainic Acid; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Receptors, Nicotinic; Receptors, Purinergic P1; Receptors, Serotonin; Ribosome Inactivating Proteins, Type 2; Toxins, Biological

Pyramidal neurones of the neocortex have been implicated in a number of neuropsychiatric diseases, such as Alzheimer's disease. Markers that may identify these cells have been investigated using a novel technique. A subpopulation of corticifugal neocortical pyramidal neurones was destroyed by the unilateral striatal injection of volkensin, a toxin that undergoes retrograde suicide transport from the site of injection. Striatal volkensin injections produced significant reductions in the number of large pyramidal neurones of the infragranular cortical layer. The selectivity of the lesion was demonstrated by the preservation of cells containing glutamic acid decarboxylase mRNA, which are considered to be cortical interneurones. Ricin, another toxic lectin, but effective as a suicide transport agent exclusively in the PNS, produced local striatal damage but no cortical cell loss. In autoradiographic binding studies of animals treated with volkensin, binding in deep neocortical layers of [3H]8-hydroxy-2-(n-dipropylamino) tetralin ([3H]8-OH-DPAT) to 5-HT1A but not of [3H]ketanserin to 5-HT2 receptors was significantly reduced. The N-methyl-D-aspartate receptor complex was investigated using the novel glycine site antagonist [3H]L-689,560, and the muscarinic M1 receptor using [3H]pirenzepine. Significant reductions in binding of [3H]L-689,560 and [3H]pirenzepine were observed in the deep neocortical layers of the animals that had been injected with volkensin. The rank order of the ligands as effective markers for this subpopulation of pyramidal neurones was [3H]8-OH-DPAT >> [3H]pirenzepine > [3H]L-689,560 >> [3H]ketanserin. These findings are thought to have advanced the understanding of the biology of pyramidal neurones. Implications for in vivo imaging treatment of neuropsychiatric conditions such as Alzheimer's disease are discussed.

Topics: Alzheimer Disease; Animals; Autoradiography; Cell Death; Disease Models, Animal; Glycoproteins; Injections; N-Glycosyl Hydrolases; Neurons; Plant Lectins; Plant Proteins; Pyramidal Tracts; Rats; Rats, Sprague-Dawley; Receptors, Neurotransmitter; Receptors, Serotonin; Ribosome Inactivating Proteins, Type 2; Toxins, Biological