Biomedical subjects

V Bigl

Publications and source records attributed to V Bigl.

At least 73 records · Page 4Linked to original sources

PubMed1995

Differential changes in cholinergic markers from selected brain regions after specific immunolesion of the rat cholinergic basal forebrain system.

The aim of this study was to characterize the effects of cortical cholinergic denervation on cholinergic parameters in the cerebral cortex and basal forebrain using a novel immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor armed with cytotoxin saporin) to efficiently and selectively lesion cholinergic neurons in rat basal forebrain. Seven days following an intracerebroventricular injection of the cholinergic immunotoxin 192IgG-saporin the binding levels of nicotinic and M1- and M2-muscarinic acetylcholine receptors (mAChR), high-affinity choline uptake sites, as well as the m1-m4 mAChR mRNA were determined in coronal brain sections by both receptor autoradiography and in situ hybridization, and quantified by image analysis. Hemicholinium-3 binding to high-affinity choline uptake sites was decreased by up to 45% in all cortical regions and in the hippocampus after a single injection of the immunotoxin compared to controls. In contrast, M1-mAChR sites were increased over the corresponding control value in the anterior parts of cingulate, frontal, and piriform cortex by about 20%, in the hindlimb/forelimb areas (18%), in the parietal cortex (35%), in the occipital cortex area 2 (17%), as well as in the temporal cortex (25%) following immunolesion. M2-mAChR levels were found to be significantly increased in the posterior part of the parietal cortex area 1 (by about 22%) and in the occipital cortex area 2 (20%) only. With respect to laminar cortical localization, M2-mAChRs and choline uptake sites were altered in all cortical layers, whereas M1-mAChRs were preferentially affected in the upper cortical layers by the immunolesion. The increase in M1-mAChR binding in the temporal and occipital cortex as a consequence of the immunolesion was complemented by an increase in the amount of m1 and m3 mAChR mRNA of about 20% in these regions. The elevated levels of M2-mAChR sites in the occipital and temporal cortex following immunolesion were accompanied by an increase in the m4 (by 25%) but not m2 mAChR mRNA. There was no effect of the immunolesion on the m1-m4 mAChR mRNA in frontal cortical regions. in the basal forebrain, however, immunolesioning caused about a 40% decrease in the level of m2 mAChR mRNA in the medial and lateral septum as well as in the vertical and horizontal limb of the diagonal band, whereas M1- and M2-mAChR binding and the levels of m1, m3, and m4 mAChR mRNA were not affected by the immunolesion in any of the basal forebrain nuclei studied.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Digoxigenylated primary antibodies for sensitive dual-peroxidase labelling of neural markers.

This study extends the application of the digoxigenin-anti-digoxigenin (DIG) technique to immunocytochemistry by using digoxigenin-tagged primary antibodies. Certain features of this technique when applied to non-radioactive in situ hybridization, such as the absence of endogeneous digoxigenin immunoreactivity in animal tissues, seem to be advantageous also for its application to immunocytochemistry. Thus, the present work is focused on dual-peroxidase staining experiments based on digoxigenylated antibodies directed against glial fibrillary acidic protein, parvalbumin, and calbindin, in a straightforward combination with conventional cytochemical methods. The protocols include the concomitant detection of two antigens, for which only primary antibodies from one animal species are available, with differently haptenized antibodies (e.g., biotinylated anti-calbindin and digoxigenylated anti-parvalbumin). The versatility of the DIG technique is exemplified by the combination of lectin and immunocytochemical procedures for the detection of astrocytes and microglia, and the simultaneous visualization of perineuronal nets and parvalbumin-containing neurons in the rat brain.

Animals↗

PubMed1995

192IGG-saporin-induced selective lesion of cholinergic basal forebrain system: neurochemical effects on cholinergic neurotransmission in rat cerebral cortex and hippocampus.

A novel cholinergic immunotoxin (conjugate of the monoclonal antibody 192IgG against the low-affinity nerve growth factor receptor with the cytotoxin saporin) producing selective lesions of cholinergic neurons in rat basal forebrain was applied to study its effect on hippocampal and cerebral cortical cholinergic neurotransmission. Intracerebroventricular injection of 4 micrograms 192IgG-saporin conjugate resulted in a selective loss of cholinergic cells in the basal forebrain nuclei 1 week after application, which was accompanied by decreased activities of choline acetyltransferase and by reduced high-affinity uptake of [3H]choline into cholinergic nerve terminals in the cerebral cortex and hippocampus, as well as by a significant activation of micro- and to a lesser extent of astroglial cells in the hippocampus, but hardly in the cerebral cortex.. The K(+)-stimulated release of [3H]acetylcholine from cortical and hippocampal slices of immunolesioned rats was found to be markedly decreased 1 week after injection. Cholinergic immunolesion led to enhanced cortical M1-muscarinic acetylcholine receptor numbers, but did not alter muscarinic receptor sensitivity as measured by carbachol-stimulated inositol phosphate production or phorbol ester binding to membrane-bound protein kinase C. In the hippocampal formation differential enhancements in binding levels of M1-muscarinic cholinergic receptor sites in the CA1 region and in the dentate gyrus were observed, whereas the nicotinic and M2-muscarinic receptor subtype are seemingly not affected by the immunotoxin in either of the subfields studied. Cholinergic immunolesioning did not result in any alterations in the hybridization signals for m1 through m4 muscarinic acetylcholine receptor mRNA in any region or layer of the hippocampus. The data suggest that (i) the novel cholinergic immunotoxin 192IgG-saporin is an appropriate tool to mimic cholinergic hypofunction in the hippocampal formation and cerebral cortex, and (ii) selective and specific immunolesion of cholinergic cells in medial septal nuclei differentially affects cholinergic receptors in particular hippocampal subfields.

Animals↗

PubMed1994

Ibotenic acid lesion of nucleus basalis magnocellularis differentially affects cholinergic, glutamatergic and GABAergic markers in cortical rat brain regions.

The present study was undertaken to study the effect of reduced cortical cholinergic activity on gamma-aminobutyric acid (GABA)ergic and glutamatergic mechanisms in cholinoceptive cortical target regions which are assumed to play an important role for realizing cognitive functions. The densities of cortical muscarinic cholinergic receptor subtypes and corresponding receptor genes m1 through m4, N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-isoxazole-4-propionic acid (AMPA) and kainate glutamate receptor subtypes as well as GABAA and benzodiazepine receptors were measured in rats 1 week after unilateral ibotenic acid lesion of the nucleus basalis magnocellularis (Nbm) applying quantitative receptor autoradiography and in situ hybridization. Ibotenic acid lesion resulted in a striking loss of acetylcholinesterase (AChE) staining in the lesioned Nbm which is associated with a 60% decrease in AChE staining and a 30% reduction in [3H]hemicholinium-3 binding in frontal and parietal cortical regions as well fore- and hindlimb areas ipsilateral to the lesion, being more prominent in the more rostral cortical regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied 1 week after lesion. M2-muscarinic receptor binding levels are slightly increased in the parietal cortex only. The lesion-induced increase in parietal cortical M2-muscarinic receptor binding is complemented by an increase in the hybridization signal for the corresponding m4-mRNA transcript. In cortical regions displaying a reduced activity of AChE and decreased levels of high-affinity choline uptake sites due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned brain side whereas AMPA and kainate binding has been significantly increased in these regions. Muscimol binding to GABAA receptors was increased in the rostral portions of frontal and parietal cortices as compared with the unlesioned brain side. Binding levels of benzodiazepine receptors were not affected by the lesion in any of the cortical regions studied. The differential changes in glutamate and GABA receptor subtypes following lesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect both glutamatergic and GABAergic functions with different intensity and different directions.

Acetylcholine↗

PubMed1994

Cortical areas are revealed by distribution patterns of proteoglycan components and parvalbumin in the Mongolian gerbil and rat.

Cortical areas in rodents have been basically characterized by its cytoarchitecture, connectivity or by physiological parameters. In this study we show that they are revealed by distribution patterns of proteoglycans and parvalbumin-immunoreactivity. Brains of young adult Mongolian gerbils (Meriones unguiculatus) and Wistar rats were cut into series of transversal sections. Proteoglycan components were detected using the N-acetylgalactosamine binding Wisteria floribunda agglutinin (WFA) and antibodies against chondroitin sulphate proteoglycan (CSPG). Differences between cortical areas were found to exist with regard to the occurrence and the density of perineuronal nets, but were also expressed in varying staining intensities for WFA and CSPG of the neuropil. Primary neocortical areas (somatosensory, auditory, visual cortex) were characterized by an intense neuropil staining in layer IV and the upper part of layer VI. Using the same methods strong labelling was also typical of the neuropil in the retrosplenial cortex, of layer Ia in the prepiriform cortex and the hippocampal CA3 field. In tangential sections cut from gerbil cortical hemispheres, some of the heavily lectin-stained cortical areas were sharply delineated from adjacent faintly labelled regions, others showed more diffuse borders. In the rat, the area-specific staining for WFA was less clearly expressed than in the gerbil. Immunocytochemistry of the calcium-binding protein parvalbumin in alternate sections showed labelling patterns of neuropil which resembled those of WFA-binding and CSPG-immunoreactivity in the entire neocortex and hippocampus. From these results it can be concluded that functional peculiarities of cortical fields may not only be determined by neuronal network parameters but also by the spatial arrangement of extracellular matrix proteoglycans.

Animals↗

PubMed1994

Differential expression of immediate early genes in distinct layers of rat cerebral cortex after selective immunolesion of the forebrain cholinergic system.

The aim of this study was to show whether reduction or loss of cortical cholinergic activity results in any particular change in the expression of the proto-oncogenes c-fos and/or c-jun. To produce cortical cholinergic hypofunction, the monoclonal antibody, 192IgG, to the low-affinity nerve growth factor receptor p75NGFR coupled to a cytotoxin, saporin, was used as an efficient and selective immunotoxin for cholinergic neurons in rat basal forebrain. Brain sections of adult rats that had received an intracerebroventricular injection of 4 micrograms of the 192IgG-saporin were subjected to in situ hybridization using oligonucleotides to detect c-fos and c-jun mRNA. Autoradiographs obtained were evaluated by quantitative image analysis. Seven days following injection of the immunotoxin there was a dramatic loss in acetylcholinesterase staining in frontal, parietal, piriform, temporal, and occipital cortices, hippocampus, and olfactory bulb, but not in the striatum and cerebellum. In situ hybridization revealed a considerable increase in the level of c-fos mRNA in the lateral septum following the cholinergic lesion, whereas in the medial septum both c-fos and c-jun mRNA were elevated. Immunolesioning led to a distinct and specific increase in the level of c-jun but not c-fos mRNA in the parietal and occipital cortex that was restricted to cortical layer IV. These data suggest that reduced cortical cholinergic activity differentially regulates expression of c-fos/c-jun genes in distinct cortical regions of the rat brain.

Acetylcholinesterase↗

PubMed1994

Digoxigenin-tagged anti-GFAP and multiple labelling of human glia, vessels and beta-amyloid.

Cytochemical procedures for the combined demonstration of astroglia, microglia, blood vessels and beta-amyloid in the human brain were developed. These multiple label experiments include the first adaptation of the digoxigenin-antidigoxigenin technique to immunocytochemistry by using digoxigenylated antibodies directed against the glial fibrillary acidic protein and its visualization in astrocytes with an antidigoxigenin-peroxidase conjugate and diaminobenzidine as chromogen. Furthermore, the specific labelling of microglial cells was performed with the novel enhanced polymer one-step staining technique, non-interfering with conventional detection systems. The demonstration of spatial relationships between glial and vascular components in normal tissue and their alterations, e.g. in Alzheimer's disease, might provide insights into the time course and localization of pathological events.

Alzheimer Disease↗

PubMed1994

Chondroitin sulfate proteoglycan-immunoreactivity of lectin-labeled perineuronal nets around parvalbumin-containing neurons.

Perineuronal nets represent highly specialized glial and glia-associated structures. In this study, a triple fluorescence labeling of chondroitin sulfate proteoglycan-immunoreactive (CSPG-ir) and N-acetylgalactosamine (GalNac)-specific plant lectin Wisteria floribunda agglutinin (WFA) binding net components as well as parvalbumin-immunoreactivity (-ir) was performed. It was shown in the rat cortex, that the same nets frequently surrounding parvalbumin-ir neurons are stained by CSPG-ir as well as by the lectin binding method.

Animals↗

PubMed1994

Receptor function in cortical rat brain regions after lesion of nucleus basalis.

The present study was undertaken to study the interaction of cholinergic and glutamatergic mechanisms in cholinoceptive cortical target regions which is assumed to play an important role for realizing cognitive functions. The densities of cortical muscarinic cholinergic receptor subtypes and corresponding receptor genes m1 through m4, as well as NMDA, AMPA and kainate glutamate receptor subtypes were measured in rats one week after unilateral mechanical lesion of the anterior part of the nucleus basalis magnocellularis (NbM) applying quantitative receptor autoradiography and in situ hybridization. The studies revealed that in cortical regions displaying a low amount of acetylcholinesterase activity due to forebrain cholinergic lesion, NMDA receptor binding was markedly reduced in comparison to the unlesioned side, whereas AMPA and kainate binding has been significantly increased in these regions. M1-muscarinic cholinergic receptor binding was not changed in any of the cortical regions studied, whereas M2-receptor densities are slightly reduced in frontal and parietal cortices following lesion. These alterations in cortical M2-muscarinic receptor binding are complemented by corresponding changes in the m2- and m4-mRNA transcripts. The comparison of binding profiles through selected cortical regions of both lesioned and normal brain side revealed that lesion of the NbM affects NMDA receptors in all cortical layers of the lesioned side, whereas AMPA receptors are affected preferentially in the upper and kainate receptors preferentially in the middle and deeper cortical layers. The differential changes in glutamate receptor subtypes following lesion might be regarded as the consequence of a cortical reorganization compensating for the reduced cholinergic presynaptic input. The data further suggest that presynaptic cortical cholinergic deficits might affect glutamatergic functions with different intensity and different directions.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Potentiating and depressant effects of metabotropic glutamate receptor agonists on high-voltage-activated calcium currents in cultured retinal ganglion neurons from postnatal mice.

This study was aimed at clarifying the role of metabotropic glutamate receptors (mGluRs) in the regulation of intracellular Ca2+ concentration ([Ca2+]i in postnatal mouse retinal ganglion neurons (RGNs). RGNs were maintained for 1-2 weeks in vitro by adding brain-derived neurotrophic factor (BDNF) and basic fibroblast growth factor (bFGF) to the culture medium. In order to select these cells for electrophysiological measurements, RGNs were vitally labelled with an antibody against Thy-1.2. Voltage-activated Ca2+ currents [ICa(V)] were recorded with patch electrodes in the whole-cell configuration. It was found that racemic +/--1-amino-cyclopentane-trans-1,3-dicarboxylic acid (t-ACPD) or its active enantiomer 1S,3R-ACPD rapidly and reversibly either enhanced or depressed ICa(V). Quisqualate (QA), L-2-amino-4-phosphonobutyrate (L-AP4) and the endogenous transmitter glutamate induced similar effects when ionotropic glutamate receptors were blocked with D-2-amino-5-phosphonovalerate (D-APV) and 6,7-dinitroquinoxaline-2,3-dione (DNQX). omega-Conotoxin GVIA (omega-CgTx GVIA), but not nifedipine prevented modulation of ICa(V) by mGluR agonists. The depression of ICa(V) by t-ACPD was irreversible when cells were dialysed with guanosine-5'-O-(3-thiotriphosphate) (GTP[gamma-S]). Ratio measurements of fura-2 fluorescence in Thy-1+ cells showed that neither t-ACPD, QA nor L-AP4 affected [Ca2+]i by liberation of Ca2+ from intracellular stores. Our results suggest that cultured RGNs express mGluRs. These receptors cannot induce Ca2+ release from intracellular stores but regulate [Ca2+]i by a fast and reversible, G-protein-mediated action on a subpopulation of voltage-activated Ca2+ channels.

Alanine↗

PubMed1994

Postnatal development of NMDA, AMPA, and kainate receptors in individual layers of rat visual cortex and the effect of monocular deprivation.

The postnatal development of the ligand binding to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), and kainate receptor sites was studied in individual layers of rat visual cortex with [3H]MK-801, [3H]CNQX and [3H]kainate, respectively. The studies were performed by quantitative receptor autoradiography in the different visual cortical layers from normally raised rats and from monocularly deprived animals. In normally raised rats, in all visual cortical layers, [3H]MK-801 and [3H]CNQX binding increased significantly from birth to around postnatal day 20, at which age already the adult values are reached. In contrast, the increase in [3H]kainate binding from day 1 to day 15 is followed by a significant decrease in binding sites up to day 25; at this age the adult binding level is nearly attained. Monocular deprivation, by unilateral eyelid suture at the age of 11 days onwards, leads to a transient decrease in [3H]CNQX binding in all visual cortical layers, whereas [3H]kainate binding results to a permanent decrease in AMPA receptor sites in cortical layers II to VI in both sides of the cortex. In contrast, only long-term monocular deprivation until the age of 90 days resulted in decreased [3H]MK-801 binding levels as compared to age-matched controls. The data suggest that the laminar development of glutamate receptor subtypes is differentially affected by visual experience during early brain maturation.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1994

Projection of non-cholinergic basal forebrain neurons ensheathed with perineuronal nets to rat mesocortex.

The existence of non-cholinergic (GABAergic) components in the septo-hippocampal system but also in basal forebrain projections terminating in the olfactory bulb and certain cortical areas has been documented by several authors using retrograde and anterograde tracing techniques. On the other hand, the basal forebrain also contains a high number of mainly parvalbumin-positive neurons ensheathed by a lattice-like matrix of polyanionic proteoglycans forming so-called perineuronal nets of as yet unknown function. By a combination of retrograde tracing using Fluoro-Gold injection into mesocortical areas of rats and staining of perineuronal nets by Wisteria floribunda agglutinin (WFA) the present study describes the projection pattern and distribution of non-cholinergic projection neurons characterized by perineuronal nets in the anterior parts of the basal forebrain complex (medial septal nucleus, nucleus of the diagonal band of Broca, magnocellular preoptic nucleus). After tracer injection into the cingulate cortex labelled net-associated neurons were distributed within the rostrocaudal extension of the basal forebrain complex but were predominantly found in the horizontal limb of the diagonal band of Broca. Retrograde labelling of neurons with perineuronal nets after tracer injection into the retrosplenial cortex was more pronounced in the medial septum. Choline acetyltransferase-immunoreactive (ChAT-ir) projection neurons were in no case associated with perineuronal nets. The results demonstrate that a large portion of the non-cholinergic projection neurons of the basal forebrain are endowed with a specialized microenvironment of proteoglycans and form a strong input system of mesocortical components of the limbic system.

Animals↗

PubMed1994

Muscarinic acetylcholine receptor subtypes in rat visual cortex--a comparative study using quantitative receptor autoradiography and in situ hybridization.

The laminar pattern of M1- and M2-muscarinic acetylcholine receptors (mAChR) in rat visual cortex has been compared with the distribution of the corresponding m1, m2, m3 and m4 receptor genes using both quantitative receptor autoradiography and in situ hybridization histochemistry. The laminar distribution of 3H-pirenzepine binding to M1-mAChRs in rat visual cortex shows a bimodal pattern with higher binding levels in upper layer III and deeper layer VI. In contrast, highest binding of 3H-AF-DX384 to M2-mAChRs was observed in upper layer IV (100%) and upper layer VI (about 80% of highest binding). The m1 receptor mRNA is almost homogeneously distributed throughout the visual cortex, whereas the m2mAChr mRNA predominates in layer IV with lower levels in layers I and V. The highest amounts of m3mAChR mRNA in rat visual cortex were observed in layer II, while the distribution of m4mAChR transcripts shows a bimodal pattern with peaks in layers III and upper layer VI. The distinct laminar pattern of mRNA muscarinic receptor subtypes in rat visual cortex suggest specific roles of the muscarinic receptor in visual function.

Animals↗

PubMed1993

Distribution of parvalbumin-containing neurons and lectin-binding perineuronal nets in the rat basal forebrain.

In sections of rat brain treated for Wisteria floribunda agglutinin (WFA) labelling the occurrence of parvalbumin (PARV)-, calbindin (CALB)- or choline acetyltransferase (ChAT) immunoreactivity was analyzed in the basal forebrain using dual-peroxidase and double-fluorescence methods. Only PARV-immunoreactive (-ir) neurons were surrounded by WFA-labelled, i.e. N-acetylgalactosamine-containing, perineuronal lattice-like structures known as perineuronal nets. The distribution of these nets and PARV-ir cells in the rat basal forebrain was documented to obtain detailed data on their co-existence. A remarkable diversity in distribution of both markers was observed, as PARV-ir neurons are only associated with nets in the medial septal nucleus, the nuclei of the diagonal band and the magnocellular preoptic nucleus, but not in the ventral pallidum or the substantia innominata/nucleus basalis complex. These differences in the neuronal microenvironment may reflect system-related specializations of neurons within the basal forebrain nuclei.

Animals↗

PubMed1992

Changes in acetylcholinesterase and butyrylcholinesterase in Alzheimer's disease resemble embryonic development--a study of molecular forms.

The pattern of molecular forms of acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholinesterase (BChE, EC 3.1.1.8) separated by density gradient centrifugation was investigated in the brain and cerebrospinal fluid in Alzheimer's disease (AD), in human embryonic brain and in rat brain after experimental cholinergic deafferentation of the cerebral cortex. While a selective loss of the AChE G4 form was a rather constant finding in AD, a small but significant increase of G1 for both AChE and BChE was found in the most severely affected cases. Both in normal human brain and in AD a significant relationship could be established between the AChE G4/G1 ratio in different brain regions and the activity of choline acetyltransferase (ChAT). A similar decrease of the AChE G4 form as observed in AD can be induced in rat by experimental cholinergic deafferentation of the cerebral cortex. The increase in G1 of both AChE and BChE in different brain regions in AD is quantitatively related to the local density of neuritic plaques which are histochemically reactive for both enzymes. In human embryonic brain, a high abundance of G1 and a low G4/G1 ratio for both AChE and BChE was found resembling the pattern observed in AD. Furthermore, both in embryonic brain and in AD AChE shows no substrate inhibition which is a constant feature of the enzyme in the adult human brain. It is, therefore, concluded that the degeneration of the cholinergic cortical afferentation in AD as reflected by a decrease of AChE G4 is accompanied by the process of a neuritic sprouting response involved in plaque formation which is probably associated with the expression of a developmental form of the enzyme.

Acetylcholinesterase↗

PubMed1991

Neuroscience in the former GDR.

Until 1945, when Germany was subdivided into four occupied territories, scientific traditions and science policy were the same throughout Germany. Then came 45 years of increasing separation and diverging development. Now, the East and West are again formally united and their inhabitants are experiencing, with an intensity that was not anticipated, just how different their countries have become.

Academies and Institutes↗

PubMed1991

Cholinergic neurons of the central nervous system: morphofunctional aspects.

Impairment of central cholinergic function is an early and constant finding in a number of mental disorders associated with amnesia or dementia. Although knowledge of the detailed functional implications of cholinergic mechanisms in cognition is still very incomplete, some recent results and concepts about the morphofunctional organization of the cholinergic basalo-cortical projection system are reviewed. This cholinergic system is quite different from other so-called unspecific subcortical projection systems and might have some bearing on understanding the role of cholinergic mechanisms in cognitive function and its disorders.

Acetylcholine↗

PubMed1991

Maintenance of neuronal plasticity in the reticular core and changes in trophic activity in Alzheimer's disease.

1. Neuronal loss in Alzheimer's disease (AD) is accompanied by a proliferative response of the remaining neurons. 2. Different cell types are differently involved in the process of degeneration and proliferation in AD. 3. The extent of dendritic growth in AD is related to the formation of amyloid, not preamyloid. 4. Proliferative changes similar to those observed in AD can be induced in an animal model as a response to neuronal death. 5. The processes of degeneration and proliferation in AD are probably associated with an increase in trophic activity.

Aged↗