Alzheimer's disease: a biologist's perspectives.
Explore the source record for details and available documents.
Alzheimer Disease↗
Biomedical subjects
C E Finch
Publications and source records attributed to C E Finch.
Altered tubulin distribution in the hypothalamus of aging female C57BL/6J mice.
The effects of age and estradiol on hypothalamic content and distribution of tubulin and calmodulin were examined by radioimmunoassay in ovariectomized C57BL/6J female mice. A small (14%) increase in particulate tubulin, but not soluble tubulin, was found in the hypothalamus of reproductively senescent mice (20 months) compared to young (8 months) controls. This alteration was limited to tubulin; calmodulin content was unaffected by age. Post-castration serum LH levels were lower in old, ovariectomized controls relative to young controls, but physiologic levels of estradiol, achieved by subcutaneous implants, suppressed LH levels in both age groups. In contrast to LH and uterine weight, hypothalamic tubulin and calmodulin were unaffected by estradiol treatment. These results suggest that the negative feedback effect of estradiol on LH secretion is exerted by a mechanism other than redistribution of hypothalamic tubulin or calmodulin, or that changes are restricted to a discrete sub-population of neurons.
Aging↗
Senescent change in tissue weight and immunoreactive beta-endorphin, enkephalin, and vasopressin in eight regions of C57BL/6J mouse brain and pituitary.
Tissue weights and immunoreactive (IR) content and concentration of beta-endorphin, enkephalin, and vasopressin were assayed for senescent change in anterior pituitary, neurointermediate pituitary, hypothalamus, hippocampus, striatum, dorsolateral cortex, and pons-medulla, as well as residual brain samples remaining after the other dissections. Groups of naive male C57BL/6J mice, 8-12 months old and 28-32 months old, served as subjects. Old mice exhibited significant decline in anterior pituitary and hippocampus weight. Significant increases with age were found in pons-medulla weight. IR beta-endorphin content decreased in hypothalamus and neurointermediate pituitary. IR enkephalin decreased in striatum and dorsolateral cortex. IR vasopressin content increased in hypothalamus and residual brain. Assays were replicated in later experiments using additional subjects, for total Ns of up to 54 mice. Although significant overall results were always consistent in direction from replication to replication, the magnitude of age change exhibited considerable variability. Such results suggest that single experiments on age changes in neuropeptides, particularly those giving negative results, should be carefully scrutinized and replicated before their acceptance as evidence for a transmitter's stability or instability throughout the lifespan.
Aging↗
Delayed anovulatory syndrome induced by estradiol in female C57BL/6J mice: age-like neuroendocrine, but not ovarian, impairments.
These studies describe induction of a delayed anovulatory syndrome (DAS) by estradiol (E2) in female C57BL/6J mice. Six days after birth, female mice were injected s.c. with 0.1 micrograms estradiol benzoate or oil. Over 90% of the oil-injected controls exhibited estrous cycles from 2 to 9 mo of age. In contrast, 60% of the E2-injected mice exhibited estrous cycles at 2 mo of age but were acyclic by 9 mo; these mice were considered to have exhibited a DAS, and had longer cycles than controls. At 12 mo, ovarian impairments were assessed by examining 1) ovulation after s.c. injection of 5 IU human chorionic gonadotropin (hCG), and 2) estrous cycles after grafting into young (3-mo-old) hosts. Simultaneously, neuroendocrine impairments were assessed by examining 1) the surge of luteinizing hormone (LH) induced by E2 implants after ovariectomy, and 2) estrous cycles after receiving ovarian grafts from 3-mo-old mice. Ovaries from DAS and control mice ovulated equally in response to hCG. Ovaries from DAS mice grafted into young ovariectomized hosts supported 30% more cycles, of shorter period, compared with ovaries from control donors. However, the E2-induced LH surge was 50% smaller in DAS mice than in controls. Ovariectomized DAS hosts with ovarian grafts from young mice supported 70% fewer estrous cycles, of longer period, compared with ovariectomized control hosts with young grafts. We conclude that the E2-induced DAS in female mice is not due to ovarian impairments, but seems to result from neuroendocrine impairments.
Aging↗
Elevated density of [3H]imipramine binding in aged human brain.
Aging was associated with an increase in the density of specific binding sites for [3H]imipramine in postmortem specimens of human hypothalamus, frontal cortex, and parietal cortex. In general, [3H]imipramine binding was not affected by factors considered difficult to control in postmortem studies, i.e., time from death to autopsy and cause of death. The in vitro regulation of [3H]imipramine binding by sodium was impaired with age in hypothalamic homogenates. In vitro regulation of [3H]imipramine binding by chloride was intact. Determination of the concentrations of 5-hydroxytryptamine (serotonin) and 5-hydroxyindoleacetic acid in hypothalamus and frontal cortex indicated no apparent age-related changes in indole metabolism. The age-related increase in brain [3H]imipramine binding and impairment in the in vitro regulation of binding by ions are similar to changes observed previously in aged mouse brain. The increase in brain antidepressant binding sites is discussed in relationship to other indices of brain serotonergic function in aging and to the relationship of [3H]imipramine binding and depression.
Adolescent↗
The antiestrogen LY117018 blocks effects of estradiol on pituitary glucose-6-phosphate dehydrogenase specific activity and on serum LH.
Neuroendocrine effects of the antiestrogen LY117018 were investigated in C57BL/6J mice. A series of subcutaneous injections of 17 beta-estradiol (E2) into ovariectomized mice increased pituitary glucose-6-phosphate dehydrogenase (G6PDH) specific activity, increased uterine wet weight, and suppressed the postovariectomy rise in serum LH. Simultaneous administration of LY117018 completely reversed the effects of E2 on G6PDH activity and uterine weight, and partially reversed the negative feedback of E2 on luteinizing hormone (LH). When administered in the absence of E2, LY117018 had no effect on G6PDH activity or serum LH, but increased uterine weight by 70%. Thus, LY117018 effectively antagonizes the effects of E2 at both uterine and pituitary levels, but acts as a partial agonist only in the uterus.
Animals↗
Age-correlated and ovary-dependent changes in relationships between plasma estradiol and luteinizing hormone, prolactin, and growth hormone in female C57BL/6J mice.
Impairments in the estradiol (E2)-induced surge of LH occur as aging female rodents lose reproductive cycles. These and other impairments can be substantially attenuated by ovariectomy of the young adult. In female rats, plasma PRL tends to increase with age, whereas in male rats, GH tends to decrease; PRL is regulated by E2, whereas GH is probably not. To determine if age-correlated neuroendocrine impairments are accompanied by altered neuroendocrine sensitivity to E2, the relationships among plasma E2, LH, PRL, and GH were assessed in 6- and 12-month-old cycling and 18-month-old acyclic female C57BL/6J mice given E2 implants. An additional 18-month-old group, ovariectomized at 6 months of age, was examined to determine if age-correlated changes in sensitivity to E2 are ovary dependent. One week after ovariectomy, mice were given different sized E2 implants which generated a physiological range of plasma E2. Three weeks after implantation, plasma E2 correlated positively with implant size, uterine weight, and PRL, but correlated negatively with LH in each age group; age did not affect plasma E2 levels. The suppression of LH by E2 decreased progressively with age. Conversely, the elevation of PRL by E2 increased with age. These effects of age were largely prevented by ovariectomy at 6 months of age. Plasma GH decreased slightly with age, but was not significantly affected by E2; old mice ovariectomized when young had lower GH levels than previously intact old mice. GH also correlated positively with LH in all age groups. We conclude that neuroendocrine responses to E2 are altered with age even before estrous cycles are lost. Sensitivity to E2 may either increase or decrease, depending on the function. These effects of age can be attenuated by prolonged ovariectomy. Thus, chronic exposure to ovarian E2 during normal reproductive cycles may alter neuroendocrine sensitivity to E2, which may lead to age-correlated impairments in reproductive function.
Age Factors↗
Hyperprolactinemia fails to increase striatal dopamine receptors in male and female C57BL/6J mice.
Mice were administered prolactin by either homotypic anterior pituitary grafts (4 weeks) or subcutaneous osmotic pumps containing ovine prolactin (1 week). The pituitary grafts produced considerably greater elevations of circulating prolactin than the osmotic pumps. In neither case was any change detected in striatal [3H]spiperone binding to dopamine receptors. These results are discussed in the context of contradictory evidence obtained with rats.
Animals↗
Serotonin-2 binding sites in human frontal cortex and hippocampus. Selective loss of S-2A sites with age.
Serotonin (S-2) binding sites were characterized in human frontal cortex and hippocampus throughout the lifespan. We found that the S-2 binding sites (labeled by [3H]spiperone and displaced by ketanserin) consisted of two subtypes (S-2A and S-2B) which are discriminated by competition with methysergide. The total S-2 sites in frontal cortex had a Bmax of 360 fmol/mg protein, which is approximately twice that of the hippocampus (160 fmol/mg protein). The density of total S-2 sites decreased with age in the frontal cortex of normal adults (17-100 years, n = 24). The receptor loss was primarily in the S-2A subclass. This loss of S-2A sites occurred primarily after 60 years and decreased to 50% of young adult values by the 10th decade. In the hippocampus, S-2A binding sites decreased with age, but no effects on total S-2 or S-2B sites were detected. A study of infant brains suggested the S-2A subtype in frontal cortex increases postnatally. However, in the infant hippocampus the S-2 binding approximated adult levels.
Adolescent↗
Topochemical localization of choline acetyltransferase and acetylcholinesterase in mouse brain.
The specific activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) were measured at neuroanatomically identified loci of the C57BL/6J mouse brain. ChAT specific activity was highest in corpus striatum. Areas of the basal forebrain had high to moderate activities, while low activities were seen in hypothalamic areas. AChE specific activity correlated highly with ChAT specific activity in all brain regions. Pronounced rostro-caudal gradients of both ChAT and AChE specific activities were discovered in the diagonal band of Broca. Overall, the regional distribution of cholinergic markers in mouse brain closely resembles that of the rat. Systemic administration of 17 beta-estradiol (E2) had no effect on ChAT or AChE specific activities in any brain region.
Acetylcholinesterase↗
Contamination of serotonin-2 binding sites by an alpha-1 adrenergic component in assays with (3H)spiperone.
(3H)Spiperone binds to two sites in mouse cortical membranes. These binding sites are discriminated by methysergide and prazosin, but not by butaclamol, lysergic acid diethylamide, or ketanserin. One of these sites is serotonergic in nature and is the authentic S-2 binding site. The other component is adrenergic and corresponds to the alpha-1 adrenoreceptor. This alpha-1 component may be present in other S-2 binding assays using (3H)spiperone, or (3H)ketanserin. No (3H)spiperone binding to dopaminergic D-2 sites was found in mouse cortex. Methods of avoiding alpha-1 contamination of S-2 binding assays are suggested.
Animals↗
The development of mammotroph adenomas in pituitaries of aging female C57BL/6J mice.
The development of pituitary adenomas in female C57BL/6J mice was studied over the lifespan. Mammotrophs and somatotrophs, identified by immunocytochemical staining, appeared normal in 3-4 month old animals, with the exception of an occasional hypertrophic mammotroph and, in one gland, a nest of such cells. At 15 months, hypertrophic mammotrophs, somatotrophs and unstained cells occurred singly or in areas of hyperplasia; a mammotrophic adenoma was present in one gland. At 22 months, pituitaries contained mammotroph adenomas or adenomalike mammotroph clusters within hypertrophic, hyperplastic areas as seen in 15 month old glands. Pituitaries from all 28-30 month old mice contained mammotroph adenomas; nests of hypertrophic cells were present in 5 of 8 glands studied. These results suggest that mammotrophic adenomas may arise from hypertrophic mammotrophs, which are often found in nests with other hypertrophic pituitary cell types. However, this study does not exclude the possibility that mammotroph adenomas and hypertrophic mammotrophs occur independently.
Adenoma↗
Estradiol-induced adult anovulatory syndrome in female C57BL/6J mice: age-like neuroendocrine, but not ovarian, impairments.
Long-term effects of elevated plasma estradiol (E2) on ovarian and neuroendocrine functions were examined in 4-month-old cycling female C57BL/6J mice injected s.c. with 0.2 or 0.05 mg estradiol valerate (EV), or oil. Within 7 days, EV-injected mice became permanently acyclic, exhibiting the persistent vaginal cornification (PVC) characteristic of reproductive senescence in rodents. Four months after injection, ovaries from EV-injected mice exhibited no corpora lutea, but ovulated in response to an injection of human chorionic gonadotropin (hCG) (as do older, spontaneously PVC mice). When grafted into young mice, ovaries from EV-injected mice supported as many estrous cycles as ovaries from oil-injected controls. EV did not alter the suppression of luteinizing hormone (LH) by E2, LH response to injected LH releasing hormone (LHRH), or plasma prolactin (Prl). However, EV-injected mice exhibited impairments in LH regulation similar to those seen in old, acyclic mice. Plasma LH 30 days after ovariectomy was 40% lower, and E2-induced LH surges were 60% lower, in EV-injected mice versus controls. Furthermore, EV-injected mice were unable to support estrous cycles given young ovarian grafts, in contrast to controls. Effects of sustained but physiological levels (15-20 pg/ml) of plasma E2, were examined in intact cycling mice given sham or E2 implants. Six weeks after implantation, the implants were removed; only 50% of the E2-implanted mice subsequently exhibited estrous cycles, compared with 100% of sham-implanted controls. Furthermore, those E2-implanted mice which did cycle had fewer cycles than controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Longitudinal studies of estrous cyclicity in aging C57BL/6J mice: II. Cessation of cyclicity and the duration of persistent vaginal cornification.
The of onset of acyclicity and the duration of persistent vaginal cornification (PVC), the predominant postcyclic anovulatory condition, were measured in five cohorts of virgin mice staggered across a 6-yr interval. The average age of cessation of cyclicity varied significantly among cohorts, ranging from 11 to 16 mo of age. Seventy-five percent of the mice entered PVC after ceasing to cycle, the remainder entered directly into a persistent diestrous condition. The duration of PVC, which averaged between 2 and 4 mo, varied markedly among individuals and was inversely related to the age of onset of acyclicity. Consequently, the variance associated with the cessation of cyclicity was about 4-fold greater than that associated with the cessation of PVC. These differing variances suggest that the factors governing ovulatory failure and PVC cessation may differ.
Aging↗
Chronic domperidone fails to increase striatal spiperone binding sites despite hyperprolactinemia: comparison with chronic haloperidol.
Mice were administered the dopaminergic antagonists haloperidol or domperidone in their drinking water for 2 or 21 days. Serum prolactin levels and striatal 3H-spiperone-binding sites (D-2 receptors) were compared to vehicle-treated controls. While only domperidone elevated serum prolactin levels, only haloperidol increased the density of striatal 3H-spiperone-binding site. The failure of domperidone, a potent D-2 receptor antagonist, to increase striatal receptor number is attributed to its poor penetration of the blood-brain barrier. These results indicate that peripheral effects of neuroleptic drugs, including prolactin elevation, are not sufficient for the development of dopaminergic supersensitivity in the central nervous system.
Animals↗
Ovarian and steroidal influences on neuroendocrine aging processes in female rodents.
Some Mammalian aging processes involve effects of steroids on the brain and pituitary. An ovary-dependent, neuroendocrine aging syndrome of laboratory rats and mice is described in this article. This syndrome can be attenuated during aging by chronic ovariectomy and can be prematurely induced in young rodents by sustained exposure to estradiol (E2). The limited follicular stock in the ovary is proposed to be a major pacemaker of aging in this neuroendocrine syndrome; ovarian aging may interact with neuroendocrine aging. Ovary-independent neuroendocrine changes occur as well. We also discuss developmental influences on adult aging in rodents and other examples in which adult lower mammals are sensitive to long lasting effects of steroids on the brain and pituitary. Possible molecular mechanisms are considered. In view of the long lasting effects of E2 and other steroids on lower mammals, the potential for long term effects of ovarian steroids on the human brain and pituitary warrants continued evaluation.
Aging↗
The regulation of luteinizing hormone and prolactin in C57BL/6J mice: effects of estradiol implant size, duration of ovariectomy, and aging.
The induction of a LH surge by estradiol (E2) implants was characterized in ovariectomized C57BL/6J mice. Various times after ovariectomy mice were given a priming E2 implant, followed by an LH surge-inducing E2 implant, and were sampled 30 h later at darkness. The magnitude of the E2-induced LH surge was influenced by the postovariectomy interval, sizes of the implants, and age. Mice ovariectomized for 30-60 days before E2 implantation displayed larger surges than those ovariectomized for 4 days. Priming implants yielding 10 pg E2/ml plasma permitted the subsequent induction of vigorous LH surges, whereas no LH surges were observed with slightly larger priming implants that yielded 15 pg E2/ml. The size of the surge-inducing implant was correlated with the size of the subsequent LH surge. However, regardless of implant size, aging mice (8 vs. 13 months old) had smaller LH surges. Sequential daily LH surges were not observed under any conditions, suggesting that mice differ from rats and hamsters in their regulation of LH by E2. Plasma PRL was slightly elevated in the afternoon just before the LH surge, but returned to basal levels during the LH surge, indicating an uncoupling of the LH and PRL surges. The two-stage E2 implantation protocol for inducing LH surges by physiological levels of E2 allows more detailed examination of the priming vs. surge-inducing effects of E2.
Aging↗
Reproductive senescence in female C57BL/6J mice: ovarian impairments and neuroendocrine impairments that are partially reversible and delayable by ovariectomy.
Ovarian and neuroendocrine impairments were examined before and after the age-correlated loss of estrous cycles in C57BL/6J female mice. The role of ovarian secretions in inducing neuroendocrine impairments before and after the loss of estrous cycles was also examined by determining neuroendocrine impairments after prolonged ovariectomy. Young (6-month-old) cycling, middle-aged (12-, 14-, and 16-month-old) cycling or acyclic, and old (18-month-old) acyclic mice were used. Ovarian impairments were assessed by grafting old ovaries into young hosts. Neuroendocrine impairments were assessed by grafting young ovaries into middle-aged and old hosts, ovariectomized either at grafting or 2 months before, and by inducing a LH surge in mice that had been ovariectomized for 4 days, 1 month, or 2 months. One group of 16-month-old and one group of 18-month-old mice were also ovariectomized at 6 months of age; these groups were used to examine the steroid-induced LH surge. The LH surge was induced by inserting sc a single priming estradiol (E2) implant, followed by two more (surge-inducing) implants 6 days later; 33 h after the second implantation, mice were decapitated (1800 h). The number of estrous cycles supported by middle-aged and old ovaries grafted into young hosts was reduced by more than 90% compared with that in young ovaries. The number of estrous cycles supported by middle-aged and old hosts given young ovarian grafts was reduced by 60% and 90%, respectively, compared with that in young hosts. Middle-aged and old hosts also had progressively longer estrous cycles than young hosts. Levels of the E2-induced LH surge in middle-aged and old mice were also reduced by 60% and 90%, respectively, compared with levels in young mice. In old acyclic mice, ovariectomy for 2 months partially reversed impairments in the LH surge and partially restored the ability to support cycles with young grafts; these functions, normally 90% impaired in old mice, were only 60% impaired after prolonged ovariectomy. Moreover, ovariectomy 2 months before grafting in old hosts resulted in shorter estrous cycles and 60% fewer pituitary adenomas. In middle-aged cycling mice, ovariectomy for 2 months did not affect impairments in the LH surge or in the ability to support estrous cycles with young grafts; these functions remained 60% impaired in middle-aged mice ovariectomized for 2 months. If mice were ovariectomized when young, the age-correlated impairments of the E2-induced LH surge at 16 months were largely prevented.(ABSTRACT TRUNCATED AT 400 WORDS)
Aging↗