Stable vasopressin innervation in the degenerating human locus coeruleus in Alzheimer's disease
Abstract
The vasopressin (VP) innervation of the human locus coeruleus (LC) was immunocytochemically investigated in Alzheimer's disease (AD) patients and non-demented controls. A dense innervation of VP fibers was present throughout the entire rostro-caudal length of the LC in both, controls and AD-patients. The VP immunoreactivity was confined to fibers; no signs of cell body staining could be found. Comparison of five non-demented control subjects anf five AD patients on fifteen different levels throughout the LC revealed that the VP innervation of this nucleus remained intact in AD, even in the rostral part of the LC, which is the most affected region with respect to neuronal loss.
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Cited by (13)
Neurohypophyseal peptides in aging and Alzheimer's disease
2002, Ageing Research ReviewsThe neurohypophyseal hormones arginine–vasopressin (AVP) and oxytocin (OT) are produced in the neurons of the hypothalamic supraoptic (SON) and paraventricular (PVN) nucleus and in the much smaller cells of the suprachiasmatic (SCN) nucleus. The SON is the main source of plasma AVP. Part of the AVP and OT neurons of the PVN join the hypothalamo–neurohypophyseal tract, whereas others send projections to the median eminence or various brain areas, where AVP and OT are involved in a number of central functions as neurotransmitters/neuromodulators. AVP and OT from the PVN can also regulate via the autonomous innervation endocrine glands and fat tissue. OT is produced for a major part in the PVN but some OT neurons are present in the SON. Moreover, both AVP and OT containing neurons are observed in the “accessory nuclei”, i.e. islands situated between the SON and PVN. The SCN is the biological clock, and the number of AVP expressing neurons in the SCN shows both diurnal and seasonal rhythms. In addition to these hypothalamic areas, AVP and OT may be found to a lesser extent in some other brain areas, such as the bed nucleus of the stria terminalis, diagonal band of Broca, nucleus basalis of Meynert, lateral septal nucleus, globus pallidus and the anterior amygdaloid nucleus, as well as in the peripheral tissues. The AVP and OT containing neurons should not be considered as one system. Prominent functional differences exist between the different nuclei. The heterogeneity also becomes clear from the marked differences in the neurohypophyseal peptides containing neurons of the SON, PVN and SCN during aging, and in the most prevalent age-related neurodegenerative diseases, i.e. Alzheimer’s disease (AD). For those reasons, we will discuss the SON, PVN and SCN separately.
The human hypothalamo-neurohypophysial system in health and disease
1999, Progress in Brain ResearchThe present paper reviews the changes observed in the human supraoptic (SON) and paraventricular (PVN) nuclei, and their projections to the neurohypophysis, median eminence and to other brain areas in health and disease.
Brain vasopressin levels in Down Syndrome and Alzheimer's disease
1998, Brain ResearchPerforming gene hunting in Down Syndrome fetal brain we detected an overexpressed sequence highly homologous to the human vasopressin gene. As this neuropeptide may be involved in the pathogenetic mechanism and, moreover, was described to play a role in memory and learning, we decided to study the brain gene product level in Down Syndrome (DS), controls and patients with Alzheimer's disease (AD). Subtractive hybridization was used to study the differential expression between steady state mRNA levels in fetal brain of DS and controls at the 23rd week of gestation. A radioimmunological method was used to determine vasopressin (AVP) in five brain regions of each 9 aged DS brains, 9 brains with AD and 9 control individuals, obtained from brain bank. An overexpressed nucleic acid sequence with 91% homology to the vasopressin gene was detected in both fetal brains with DS. AVP levels in controls were of the order cerebellum>occipital>frontal>parietal>temporal lobe and were significantly higher in temporal lobe and lower in cerebellum of patients with DS. AVP levels in brain of AD patients were also significantly increased in temporal lobe but were not reduced in cerebellum. The biological meaning of increased AVP remain unclear but may be linked to the neurodegenerative processes, proposed to be similar in both disorders. Data from gene hunting in fetal DS brain along with our data on aged DS and AD patients suggest the early involvement of AVP in the pathomechanism accompanying cholinergic, monoaminergic and neuropeptidergic deficits described in DS and AD.
Chapter IV The primate locus coeruleus: the chemical neuroanatomy of the nucleus, its efferent projections, and its target receptors
1997, Handbook of Chemical NeuroanatomyThe nucleus locus coeruleus (LC) is a small structure located adjacent to the wall of the fourth ventricle in the pontine brainstem. Although it is composed of a limited number of cells, it is considered to be the largest collection of noradrenergic neurons in the central nervous system (CNS). The most striking feature of this nucleus is the immensity and divergence of its axonal arbors. LC efferents constitute the most divergent system of axonal arborizations found in the CNS. This characteristic permits the relatively small number of noradrenergic neurons to innervate large, functionally diverse regions of the brain and spinal cord. There is, apparently, no simple functional correlate of innervation density, with sensory and motor structures, relay and cortical areas for all sensory modalities, cortical association areas, hippocampus, and most other brain structures receiving some innervation. The most commonly used method for characterizing the distribution of LC axons has been immunohistochemistry, using primary antisera directed against dopamine-β-hydroxylase, the final synthetic enzyme for norepinephrine.
Chapter II Neurobiology and neuropathology of the human hypothalamus
1997, Handbook of Chemical NeuroanatomyThe human hypothalamus is involved in a wide range of functions in the developing, adult and aging subject and disorders and degenerative changes in this brain region are responsible for a large number of symptoms of neuroendocrine, neurological and psychiatric diseases. This review discusses the functional and chemical neuroanatomy of a number of prominent nuclei in the human hypothalamus and adjoining structures in relation to normal development, sexual differentiation, aging and a number of neuropathological disorders. In this summary references are given for some useful neurochemical markers (i.e. stainings that largely characterize the borders of a particular (sub)nucleus). The borders of the hypothalamus as such are equivocal but the present paper is not concerned with the rather arbitrary answers to the question which structure does or does not belong to the hypothalamus. Instead, it discusses the major nuclei that are present in a block of brain tissue containing the hypothalamus and adjoining areas in order to provide a basis for the neuropathology of this brain region. Most authors distinguish three hypothalamic regions: (i) the chiasmatic or preoptic region, (ii) the tuberal region, and (iii) the mamillary region.o
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PREOPTIC OR CHIASMATIC REGION. This region is thought to be important for temperature regulation, through the initiation of mechanisms that increase the loss of body heat, i.e. by sweating and vasodilatation. Acute lesions in this area may cause a rapid rise in body temperature. In this region and in adjoining areas the following nuclei are discussed:u
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The nucleus basalis of Meynert (NBM) and the Diagonal Band of Broca that, together with the medial septal nucleus, are the major sources of cholinergic innervation for the cortex, hippocampus and amygdala. Choline acetyltransferase histochemistry or immunocytochemistry stains the majority of these neurons (Pearson et al., 1983; McGeer et al., 1984; Chan-Palay, 1988b; Saper and Chelimsky, 1984). In addition, proenkephalin LHRH, delta sleep inducing peptide, vasopressin and galanin are found in NBM neurons. The NBM receives a dense innervation of at least 8 different peptides and is affected in Alzheimer's disease, Creutzfeldt-Jacob's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and PSP. In Alzheimer's disease cytoskeletal alterations, increased β-amyloid precursor expression and neurofibrillary tangles are found and the neurons of the NBM show atrophy, decreased neuronal activity, and a loss of choline acetyltransferase staining. However, there is probably no major loss of neurons. In addition, compensatory and aberrant growth phenomena are observed in the NBM in Alzheimer's disease. In Parkinson's disease Lewy bodies are found in the NBM. The NBM contains low and high-affinity receptors for nerve growth factors. The latter (i.e. Trk receptors) decrease in Alzheimer's disease.
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The islands of Calleja are characterized by a core of small (5–10 m) neurons. They are situated in the substantia innominata, dorsally to the NBM and laterally to the DBB, and contain fibers staining for cholinergic markers, catecholamines, neuropeptide-Y, substance-P and VIP. In fact, VIP innervation seems to be a good marker for the islands. In Alzheimer's disease they contain β/A4 staining amorphic plaques and cytoskeletal alterations stained by Alz-50.
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The suprachiasmatic nucleus cannot be recognized reliably in thin sections without immunocytochemistry. It is characterized by a large population of neurotensin neurons (Moore et al., 1992), while vasopressin neurons (Swaab et al., 1985) so far best reflect their functions in relation to biological rhythms and reproduction. In addition, it contains neurons that are immunoreactive for VIP, neuropeptide-Y, TRH, somatostatin, galanin and proenkephalin. Melatonin receptors are also found in the SCN area. The entraining effect of light on the SCN is mediated by a retinohypothalamic tract which contains, e.g., substance-P and teminates mainly on VIP neurons.
The SCN shows seasonal and circadian fluctuations in the number of vasopressin neurons in subjects of up to 50 years of age. Many functions show circadian and circannual fluctuations in human. Since seasonal depression and bulimia nervosa react favorably to light therapy, the SCN may be involved.
The SCN is still immature at birth. The populations of vasopressin and VIP neurons in the SCN mature, to a large extent, after birth. Fetal rhythms during pregnancy are mainly driven by the mother, although, e.g., temperature rhythms are found in some 50% of the prematurely born children. Entrainment of premature children to circadian rhythms may stimulate their development. During normal aging the seasonal and circadian fluctuations in vasopressin neurons disappear after the age of 50. The number of vasopressin expressing neurons decreases after the age of 80 and even more so and at an earlier age in Alzheimer's disease. The SCN is affected in Alzheimer's disease, which may lead to wandering, agitation and sleep disorders, that can be treated with light therapy. In addition, the retina is involved in Alzheimer's disease. Retinal cell degeneration occurs without the presence of plaques and tangles.
There are various differences in the vasopressinergic subnucleus of the SCN in relation to gender and sexual orientation. The number of VIP-expressing neurons is twice as large in men of 10 to 40 years of age as in women. The VIP difference reverses between 40 and 65 years of age. In homosexual men the vasopressin subnucleus is twice as large as in heterosexual men. VIP cell numbers in the SCN do not show a difference in relation to sexual orientation.
Other hypothalamic structures that differ in size in relation to sexual orientation are the interstitial nucleus of the anterior hypothalamus (INAH)-3, that is larger in heterosexual men than in homosexual men but for which no chemical marker is known at present, and the anterior commissure, that is larger in homosexual men than in heterosexual men and women.
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The sexually dimorphic nucleus (SDN, intermediate nucleus or INAH-1) is located between the supraoptic and paraventricular nucleus. In young adult men this nucleus is twice as large as in adult women. The human SDN contains galanin and TRH-expressing fibers and neurons (Fliers et al., 1994; Gai et al., 1990), just like the rat SDN. In addition it contains a high packing of preproenkephalin. At term, only 20% of the SDN cell number is present. At that moment cell numbers are similar in boys and girls. Postnatally 80% of the SDN cells are formed, whereas exhaustion of the matrix layer around the third ventricle is already complete around 23 weeks of gestation. The source of the majority of SDN cells is thus not clear. The difference between the SDN of men and women arises between about 4 years of age and puberty; the SDN in girls goes through a period of decreasing cell numbers. In the process of aging, a sex-dependent decrease in cell number occurs. In Alzheimer's disease cytoskeletal changes and amorphic β/A4 plaques are found in SDN neurons, but the decrease in neuronal number is similar to that in controls.
Other hypothalamic sexually dimorphic structures are INAH-2 and 3, and two subnuclei of the bed nucleus of the stria terminalis (see below) that are larger in males. The shape of the vasopressin subnucleus of the SCN is sexually dimorphic, and the number of VIP neurons in the SCN changes in men in an age-related way (see before). Furthermore the anterior commissure that is larger in females.
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The bed nucleus of the stria terminalis (BST) is situated on the junction of hypothalamus and septum and cellular bridges run through the hypothalamus between the BST and the amygdala. The BST contains at least two sexually dimorphic subnuclei. In the first place a ‘darkly staining posteromedial component’ (BST-dspm) that is 2.5 times larger in males than in females. Secondly, the central nucleus (BSTc or supracommissural part of the central nucleus of the BST or central sector) that is characterized by a massive immunoreactivity for somatostatin neurons and fibers and a strong VIP innervation from the amygdala (Walter et al., 1991; Zhou et al., 1995c). The BSTc is 40% smaller in women than in men. The size of the BSTc volume is independent of sexual orientation in men, but it is remarkably small (40% of the male reference group) in male-to-female transsexuals, suggesting a function in gender. The medial nucleus of the BST is characterized by less dense substance-P and neuropeptide-Y innervation, and the lateral nucleus of the BST by prominent somatostatin and enkephalin plexuses and the presence of neurophysins (Walter et al., 1991). The BST shows β/A4 amorphic plaques and Alz-50 positive cell bodies and dystrophic neurites in Alzheimer patients.
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The vasopressin and oxytocin cells of the supraoptic and paraventricular (SON and PVN) nucleus (Dierickx and Vandesande, 1979) project to the neurohypophysis where these peptides are released as neurohormones that are involved in water metabolism, sexual arousal, ejaculation, labor and lactation. One year after hypophysectomy 80% of the SON and PVN neurons is lost. Centrally projecting vasopressin neurons terminate synaptically and may regulate autonomic processes while centrally projecting oxytocin neurons may function as satiety cells. In the human PVN (i) no subnuclei containing magnocellular or parvicellular elements can be distinguished, (ii) nor can we distinguish the cells projecting to the neurohypophysis, median eminence or to other brain regions. Vasopressin and oxytocin are synthesized as part of a large precursor containing neurophysin and in the case of vasopressin also a c-terminal glycoprotein. Vasopressin is synthesized in the SON, PVN and BST, DBB, NBM, and oxytocin in the PVN and dorsal part of the SON.
Both the maternal and fetal SON and PVN are involved in the process of birth, e.g. by accelerating labor and by protecting the fetus against the stress of labor. Although the number of vasopressin and oxytocin neurons is already at an adult level at midgestation, these neurons are far from mature at term.
The magnocellular SON and PVN neurons also contain the catecholamine synthetizing enzyme tyrosine hydroxylase (TH). In adults TH positive neurons mainly colocalize with oxytocin, whereas in neonates they mainly colocalize with vasopressin, especially following perinatal hypoxia.
Animal experiments have shown that oxytocin neurons that project to the brain stem inhibit eating behavior and are the putative satiety neurons of the brain, an idea reinforced by our observations in Prader-Willi-syndrome patients — characterized by gross obesity and insatiable hunger. In these patients we found that the PVN total cell number was 38% lower and the PVN oxytocin neuron number 42% lower than in controls.
During the course of normal aging, vasopressin-expressing neurons in the PVN are activated and their number increases. In Alzheimer's disease the age-dependent activation of vasopressin neurons in the PVN is not present; their number remains stable. The number of oxytocin neurons remains unaltered in the course of aging and Alzheimer's disease. The vasopressin and oxytocin neurons of the SON and PVN are consequently a very stable cell population in aging and Alzheimer's disease. Recently frameshift mutations have been found in human vasopressin, and to a lesser degree in oxytocin neurons in the SON and PVN.
Oxytocin neuron number reductions of 40% and 20% were observed in AIDS and Parkinson's disease, respectively. The functional implications are not yet clear.
Diabetes insipidus may have different hypothalamic causes. Apart from trauma, ischemia, hemorrhage, inflammation and surgical manipulations, familial hypothalamic diabetes insipidus can be present, based upon a point mutation in the vasopressin-neurophysin-glycopeptide gene. Urine production may amount to up to 20 liters per day. Neuronal death in the SON and PVN has been reported in this disorder. In addition, an autoimmune form of diabetes insipidus exists with circulating antibodies against the vasopressin neuron cell surface. The synthesis of peptides in vasopressin cells, and to some degree also the oxytocin neurons, of the SON and PVN are affected in Wolfram's syndrome (DIDMOAD), although the vasopressinergic cells are present in normal numbers.
Parvicellular corticotropin-releasing hormone (CRH)-containing neurons in the PVN (Raadsheer et al., 1993) are moderately activated during the course of normal aging, slightly more in Alzheimer's disease and very strongly in depression and multiple sclerosis. Activation of CRH neurons has been established on the basis of an increase in the number of neurons expressing this peptide, an increased colocalization of vasopressin in CRH neurons and an increase in the amount of CRH mRNA. However, the pattern in which CRH neurons are activated differs in different disorders. CRH cells are not only involved in the regulation of the hypothalamo-pituitary adrenal axis, but project centrally as well. These centrally projecting CRH neurons may be responsible for mood changes, such as depression. The activation of vasopressin and oxytocin neurons in the PVN of depressed patients might potentiate the effects of CRH activation, while oxytocin hyperactivity might contribute to the inhibition of food intake in depression. Corticosteroid inhibits both the CRH neurons that coexpress vasopressin and those that do not.
Thyrotropin-releasing hormone (TRH)- containing neurons are not only found in the PVN (Fliers et al., 1994), but also in the SCN and SDN. A high density of TRH-positive fibers was observed in the median eminence, but even denser networks of fiber terminations were observed in a large number of other hypothalamic areas, such as the tuberomamillary nucleus and the ventromedial nucleus. This suggests a role as neurotransmitter/neuromodulator of TRH besides its neuroendocrine function.
A large number of other neuroactive compounds are found in the SON and PVN, e.g. dynorphin, predynorphin, cystatin-C, galanin, PACAP, LHRH, angiotensin converting enzyme, angiotensin binding sites, α-1 receptors, calcitonin gene related peptide, MCH, growth hormone releasing hormone, VIP, and VIP binding sites. In Sudden Infant Death Syndrome (SIDS), LHRH fibers in the PVN and periventricular nucleus were dramatically decreased.
The periventricular nucleus is characterized by somatostatin neurons projecting to the median eminence and by catecholamine-containing neurons that are pigmented by neuromelanin (Van de Nes et al., 1994; Spencer et al., 1985).
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TUBERAL REGION. This regions consists of two parts, (a) the medial tuberal region of the hypothalamus that contains the ventromedial, dorsomedial and infundibular (or arcuate) nucleus and (b) the lateral tuberal region that contains the nucleus tuberalis lateralis and the tuberomamillary nucleus.
The ventromedial nucleus (VMN) is supposed to play a role in sexually dimorphic functions and has been the target of stereotactic neurosurgery in ‘sexually deviant’ patients. The VMN is characterized by a dense network of somatostatin cells and fibers (Najimi et al., 1989). This innervation also stains with Alz-50 (Van de Nes et al., 1994). The VMN is supposed to play a role in sexually dimorphic functions. TRH shows a lateralization in this nucleus. The density of neurons in the VMN is decreased in Down's syndrome.
The dorsomedial nucleus (DMN) is hard to delineate in the human hypothalamus and at the moment no characteristic marker is known for this nucleus. It contains preproenkephalin, preprodynorphin, somatostatin, VIP binding sites and a dense catecholaminergic network.
The infundibular or arcuate nucleus is characterized by the presence of (pre)proopiomelanocortin neurons (Pilcher et al., 1988; Sukhov et al., 1995). A good marker is α-MSH (Désy and Pelletier, 1978; Pelletier et al., 1978) or galanin (Gai et al., 1990). Part of the infundibular nucleus, the subventricular nucleus, has neurons containing neurokinin-B (NKB), substance-P and estrogen receptors. In postmenopausal women these neurons in the subventricular subdivision of the infundibular nucleus is activated. The NKB neurons probably act on LHRH neurons as interneurons and may be involved in the initiation of menopausal flushes. The arcuate nucleus also contains LHRH, somatostatin, neurotensin, galanin, substance-P, growth-hormone-releasing-hormone, neuropeptide-Y, TRH fibers and binding sites, angiotensin binding sites and VIP binding sites. In addition, the arcuate nucleus contains the tuberoinfundibular catecholaminergic neurons that are tyrosine-hydroxylase positive and become pigmented in adulthood. In Parkinson's disease these dopaminergic neurons are not affected. In Down's syndrome a strong decrease in neural density and gliosis was found in the arcuate nucleus.
The nucleus tuberalis lateralis (NTL) can only be recognized in man and higher primates. It is presumed to be involved in feeding behavior and metabolism. A major peptide of this nucleus is somatostatin (Van de Nes et al., 1994; Najimi et al., 1989). The NTL also contains somatostatin mRNA and somatostatin binding sites. In Huntington's disease the majority of the NTL neurons is lost and the somatostatin content of the NTL decreases strongly. In Alzheimer's disease the NTL sometimes contains amorphic plaques and shows very strong early cytoskeletal alterations without cell loss and with intact neuronal metabolism, but the somatostatin staining is strongly diminished. From an early age onwards the NTL neurons contain a large amount of lipofuscin granules that do not seem to hamper neuronal function.
The tuberomamillary nucleus is characterized by histaminergic neurons (Airaksinen et al., 1991). In addition, TMN neurons contain galanin, acetylcholine-esterase, preprodynorphin, preproenkephalin, and dense accumulations of TRH fibers. The TMN projects to the cortex. Strong cytoskeletal changes, i.e. neurofibrillary tangles, plaques, amorphic plaques and decreased neuronal activity are found in this nucleus in Alzheimer's disease. In Parkinson's disease Lewy bodies are found in this nucleus although no neuronal loss is observed.
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POSTERIOR OR MAMILLARY REGION. This region plays a role in body heat regulation. The lateral nucleus of the corpora mamillaria contains somatostatin (Najimi et al., 1989), and the medial nucleus MAO positive neurons (Nakamura et al., 1991). In Alzheimer's disease the corpora mamillaria contain tangles, and in active chronic cases of Wernicke's encephalopathy alcohol-associated lesions are observed in the mamillary bodies in strongly varying amounts. The majority of the posterior hypothalamic nucleus neurons contain predynorphin and the incerto hypothalamic cell group (A13) is catecholaminergic.
Research on the human hypothalamus makes it clear that if hypothalamic tissue is studied, one should have at one's disposal not only information on the neurological or psychiatric disease involved, but also information on, e.g., age, hour and month of death, left or right part, sex, gender, sexual orientation and medication. Many neurological diseases show characteristic changes in the hypothalamus. The finding of strongly activated CRH neurons in depressed patients points to an important role of the hypothalamus in this disease. Other possible ‘hypothalamic diseases’ are, e.g., anorexia nervosa and bulimia.
We expect a wealth of new information in the coming period, also through the application of recent techniques such as in situ hybridization of mRNA for neuroactive compounds and receptors and postmortem tracing techniques to the human hypothalamus, and we hope that in the near future this may lead to major insights in the functional and chemical anatomy and in the neuropathology of the human hypothalamus.
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Differential vasopressin and oxytocin innervation of the human parabrachial nucleus: No changes in Alzheimer's disease
1996, Brain ResearchThe distribution of vasopressin and oxytocin immunoreactive fibers was examined in the pontine parabrachial nucleus of the human brain using purified polyclonal antibodies. The results revealed a striking predominance of vasopressin in this brain region. No obvious density difference, either in vasopressin or in oxytocin innervation, was found between Alzheimer's disease patients and matched controls. The present study corroborates other reports that suggest that in Alzheimer's disease the vasopressin innervation in the caudal part of the human brain is not affected.
The study was supported by the Foundation for Medical and Health Research (MEDIGON; Grant 900-552074), The Netherlands Organization for Scientific Research (NWO).
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Brain material was obtained from the Netherlands Brain Bank, Amsterdam (coordinator Dr. R. David). Neuropathology was performed by Prof. F.C. Stam (Netherlands Brain Bank) or Dr. W. Kamphorst (Free University, Amsterdam). The authors wish to thank Mr. G. Van der Meulen for his photographical work.