Alternative splicing in aging and Alzheimer's disease: Highlighting the role of tau and estrogen receptor α isoforms in the hypothalamus.

Human genes show the highest efficacy of alternative splicing (AS) in the brain as compared to other tissues. Within the brain, a remarkably rich diversity of AS events was identified in the hypothalamus. The AS frequency is increased in the aging brain.

Estrogen receptor α splice variant TADDI in the human supraoptic nucleus: an effect on neuronal size and changes in pneumonia.

Background: Estrogens mediate various effects in the brain not only via classical estrogen receptors (ERs) but also through their splice variants. We showed earlier that the ERα splice variant TADDI is abundantly expressed in the human hypothalamic supraoptic nucleus (SON).

Methods: In the present study we aimed at determining a possible effect of TADDI on human SON neuronal morphometric parameters in 58 control patients from 20 to 94 years old and in 26 patients with Alzheimer's disease (AD) aged 54-94 years old.

Increased Neuronal Nuclear and Perikaryal Size in the Medial Mamillary Nucleus of Vascular Dementia and Alzheimer's Disease Patients: Relation to Nuclear Estrogen Receptor α.

Background: The hypothalamic medial mamillary (MMN) and the tuberomamillary (TMN) nuclei are important hubs in memory circuits. Previous studies determining the neuronal Golgi complex size showed decreased metabolic activity of the TMN neurons in both Alzhei-mer's disease (AD) and vascular dementia (VD), and no obvious decline in the MMN of these patients.

Objectives: In the present study, we aimed at determining whether other morphometric parameters that are informative about the neuronal metabolic activity are changed in the MMN of AD and VD patients and whether they can be related to the expression of the nuclear estrogen receptor α (ERα) that can mediate neurotrophic effects of estrogens in the brain.

[Age-related peculiarities of acute cholecystitis].

In the present study the analysis of dynamics of basic laboratory parameters of patients with acute cholecystitis (AC) in the four age groups subdivided according to the WHO classification into young, middle age, elderly and senile was carried out. The most pronounced changes were found in the senile age group in which the AC was accompanied by the decreased number of erythrocytes, low hemoglobin and total protein, leukocytosis, lower percentage of lymphocytes and the highest levels of ALT, AST, bilirubin and urea. Changes in the elderly and senile groups differed and in a number of cases were opposite.

[NUCLEAR AND PERIKARYA SIZES OF THE NEURONS IN THE NUCLEUS BASALIS OF MEYNERT AND POSTERIOR HYPOTHALAMUS IN DIFFERENT AGE GROUPS].

Morphometric parameters of neuronal metabolic activity, such as the area of neuronal nuclei and perikarya and nuclear-cytoplasmic ratio, in the nucleus basalis of Meynert (NBM), tuberomamillary (TMN) and medial mammillary (MMN) hypothalamic nuclei of human subjects belonging to four age groups were studied. Statistically significant increase in the size of neuronal perikarya and their nuclei was found in elderly people aged 60-74 years. The surge in the metabolic activity of neurons in the NBM starts earlier than in the TMN and MMN, and becomes apparent morphologically in people of middle age (45-59 years).

[Lamellar complex changes in the human basal forebrain and hypothalamic nuclei neurons in different age groups].

In the present study the lamellar complex (LC, Golgi complex) changes in the major cholinergic nuclei of the human basal forebrain - the nucleus basalis of Meynert (NBM), the vertical nucleus of the diagonal band of Broca (VDB) and hypothalamus--the tuberomamillary (TMN), the medial mammillary (MMN) and supraoptic (SON) nuclei were analyzed considering the WHO aging classification. The increase in the size of the LC was present in NBM, MMN and SON in the 3rd age group of elderly people (60-74 years of age), in the VDB--in the 4th group (75-89 years of age), whereas in the TMN LC changes were not apparent. In conclusion, the WHO aging classification reflects the LC values age ranges and can be used to estimate age-related alterations of this parameter.

Transcriptional activity of human brain estrogen receptor-α splice variants: evidence for cell type-specific regulation.

Estrogen receptor α (ERα) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ERα splice variants from this group with different molecular defects: MB1 (intron retention), TADDI (small deletion between exons 3 and 4 with an insert), the Δ (deletion) 3(⁎)-7(*)/819 (complete skipping of exons 4, 5 and 6 and partial deletion of exons 3 and 7) and the Δ3-6 (lacking exons 3, 4, 5 and 6) in HeLa and M17 cells upon stimulation with (17β)estradiol or insulin-like growth factor 1 (IGF-1). In HeLa cells, all these splice variants showed the dominant negative function that was more pronounced for the TADDI.

Decreased alternative splicing of estrogen receptor-α mRNA in the Alzheimer's disease brain.

In this study we identified 62 estrogen receptor alpha (ERα) mRNA splice variants in different human brain areas of Alzheimer's disease (AD) and control cases and classified them into 12 groups. Forty-eight of these splice forms were identified for the first time. The distribution of alternatively spliced ERα mRNAs was brain area- and case-specific.

Hippocampal estrogen receptor-alpha splice variant TADDI in the human brain in aging and Alzheimer's disease.

Background/aims: Estrogen receptor-alpha (ER alpha) splice variants are important for understanding estrogen effects on the brain and estrogen therapy pitfalls. We addressed the question whether a novel ER alpha splice variant TADDI is expressed at the protein level in the human brain and whether it changes in relation to aging and Alzheimer's disease (AD).

Methods: Immunoreactivity (-ir) for TADDI was assessed on postmortem human brain material from a total of 116 cases.

Estrogen receptor-alpha splice variants in the human brain.

In the present review we discuss recent findings showing that, in addition to the canonical estrogen receptor-alpha (ERalpha), the level of various ERalpha splice variants is changed in the human brain in aging and Alzheimer's disease (AD) at both the mRNA and protein level and that they should be considered for the understanding of estrogen effects on the brain and estrogen therapy pitfalls. Indeed, the expression pattern of certain splice forms is brain area-specific. Thus, the major isoform found in the mamillary body (MB) appeared to be del.

Age-dependent ERalpha MB1 splice variant expression in discrete areas of the human brain.

A role of estrogens in brain aging and Alzheimer's disease (AD) is a hot topic of research. We show in material of 71 patients that the estrogen receptor alpha (ERalpha) splice variant MB1 is expressed at the protein and mRNA level in the human brain. MB1 is mainly confined to astrocytes, membranes and cytoplasm of projecting neurons and endothelial cells.

Alterations in the human brain in menopause.

In a series of studies we showed that menopause in women causes alterations not only in the neuronal expression of estrogen receptors (ER) alpha and beta, but also in local estrogen production in several brain areas and in the rate of neuronal metabolism. Although such changes are clearly brain region-specific, there seems to be no evidence at present for a decrease in neuronal metabolic rate. On the contrary, an increase in the neuronal metabolic activity and in the level of ERalpha in postmenopausal women was noted.

Estrogen receptor alpha and its splice variants in the hippocampus in aging and Alzheimer's disease.

Clinical and experimental studies show that estrogens can have beneficial effects on hippocampus-dependent cognitive functions that may be mediated by estrogen receptor (ER)alpha. We investigated whether menopause and Alzheimer's disease (AD) cause changes in this ER subtype. Immunocytochemical staining of ERalpha, aromatase and Golgi complex (GC) was performed on paraffin embedded hippocampal tissue from women of the pre-, peri- and postmenopausal age.

Estrogen receptor-alpha splice variants in the medial mamillary nucleus of Alzheimer's disease patients: identification of a novel MB1 isoform.

Previously we have reported an increased nuclear estrogen receptor-alpha (ERalpha) in the medial mamillary nucleus (MMN) in Alzheimer's disease (AD). In the present study, we addressed the presence of specific ERalpha mRNA splice variants in this brain area of five AD cases compared with five controls using the RT-PCR and quantitative RT-PCR approach. Indeed, the occurrence of isoforms with the deletion of exons 7 (del.

Metabolic alterations in the hypothalamus and basal forebrain in vascular dementia.

Previously, alterations in neuronal metabolism were found in a number of brain areas of Alzheimer disease (AD) patients. In the present study we aimed at determining for the first time whether metabolic changes would also occur in vascular dementia (VD) patients in the supraoptic (SON), infundibular (INF), tuberomamillary (TMN), medial mamillary nuclei, vertical limb of the diagonal band of Broca (VDB), and nucleus basalis of Meynert. The Golgi complex (GC) size, cell size, and vasopressin mRNA levels (in the SON) were used as measures of neuronal metabolic activity in postmortem material.

Diminished aromatase immunoreactivity in the hypothalamus, but not in the basal forebrain nuclei in Alzheimer's disease.

In previous studies we have shown in Alzheimer's disease (AD) an enhanced nuclear estrogen receptor (ER) alpha expression in the cholinergic basal forebrain nuclei, i.e. the vertical limb of the diagonal band of Broca (VDB) and the nucleus basalis of Meynert (NBM), and in a number of hypothalamic nuclei, i.

Estrogen receptors and metabolic activity in the human tuberomamillary nucleus: changes in relation to sex, aging and Alzheimer's disease.

The human tuberomamillary nucleus (TMN), that is the sole source of histamine in the brain, is involved in arousal, learning and memory and is impaired in Alzheimer's disease (AD) as shown by the presence of cytoskeletal alterations, a reduction in the number of large neurons, a diminished neuronal metabolic activity and decreased histamine levels in the hypothalamus and cortex. Experimental data and the presence of sex hormone receptors suggest an important role of sex steroids in the regulation of the function of TMN neurons. Therefore, we investigated sex-, age- and Alzheimer-related changes in estrogen receptor alpha and beta (ERalpha and ERbeta) in the TMN.

Increased neuronal metabolic activity and estrogen receptors in the vertical limb of the diagonal band of Broca in Alzheimer's disease: relation to sex and aging.

Changes in the interaction between sex hormones and the cholinergic system are presumed to play a role in cognitive decline in aging and Alzheimer's disease (AD). The hippocampus is one of the most strongly affected brain structures in AD and the vertical limb of the diagonal band of Broca (VDB) is its major source of innervation. In the present study we found, surprisingly, for the first time that the neuronal metabolic activity as measured by the size of the Golgi apparatus in the VDB gradually increases after the age of 50 years in controls and that this process starts earlier and is more pronounced in Alzheimer's disease patients.

Changes in metabolic activity and estrogen receptors in the human medial mamillary nucleus: relation to sex, aging and Alzheimer's disease.

The medial mamillary nucleus (MMN) is situated caudally in the human hypothalamus and is involved in memory processes. In search for putative sites of action in estrogen replacement therapy on memory both in aging and Alzheimer's disease (AD), we aimed at determining whether changes would occur in estrogen receptors (ER) or metabolic activity in the MMN neurons under these conditions in a sex-dependent way. The Golgi apparatus (GA) and cell size, that were previously shown to be good measures of changes in neuronal metabolic activity, were measured in the MMN of 10 young (20-50 years old), 11 elderly (56-76 years old) control men and women and 11 AD patients (54-78 years old).

Sexual differentiation of the human hypothalamus.

Functional sex differences in reproduction, gender and sexual orientation and in the incidence of neurological and psychiatric diseases are presumed to be based on structural and functional differences in the hypothalamus and other limbic structures. Factors influencing gender, i.e.

Sex differences in estrogen receptor alpha and beta expression in vasopressin neurons of the supraoptic nucleus in elderly and Alzheimer's disease patients: no relationship with cytoskeletal alterations.

In various hypothalamic and adjacent brain regions we have previously found a remarkable increase in nuclear estrogen receptor staining in Alzheimer's disease (AD). In order to see whether this was a general phenomenon or rather specific for those areas that are affected by the AD process we investigated ERalpha and ERbeta expression in the arginine-vasopressin (AVP) neurons of the human dorsolateral suparoptic nucleus (dl-SON), that is the major source of plasma AVP. These neurons remain exceptionally intact in AD.

Sex differences in androgen receptor immunoreactivity in basal forebrain nuclei of elderly and Alzheimer patients.

The vertical limb of the diagonal band of Broca (VDB or Ch2) and the nucleus basalis of Meynert (NBM or Ch4) are major cholinergic nuclei of the human basal forebrain, a complex that is affected in Alzheimer's disease (AD). Sex hormones influence the function of these cholinergic neurons in animals and humans and we showed earlier that estrogen and androgen receptors (AR) are present in both the VDB and the NBM of young patients of 20-39 years of age. The aim of the present study was to investigate whether AR expression changes in relation to aging and AD.

Neurohypophyseal peptides in aging and Alzheimer's disease.

The 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.

Structural and functional sex differences in the human hypothalamus.

Sex differences in the brain may be the basis not only for sex differences in reproduction, gender identity (the feeling of being male or female), and sexual orientation (heterosexuality vs homosexuality), but also for the sex difference in prevalence of psychiatric and neurological diseases ( Swaab and Hofman, 1995 ). In this brief article we discuss a few examples of structural and functional sex differences in the human brain.

Increased expression of estrogen receptor alpha and beta in the nucleus basalis of Meynert in Alzheimer's disease.

The human nucleus basalis of Meynert (NBM) is severely affected in Alzheimer's disease (AD). Since estrogens may reduce both the risk and severity of AD, possibly by an action on the cholinergic system, we determined whether estrogen receptors are present in the human NBM and what their changes are in normal aging and in AD. ERalpha was expressed to a higher degree than ERbeta and was localized mainly in the cell nucleus, while ERbeta was mainly confined to the cytoplasm.