Inflammatory mechanisms and anti-inflammatory therapy in Alzheimer's disease.
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.
Evolutionary perspectives on amyloid and inflammatory features of Alzheimer disease.
We propose that the amyloid deposits in senile plaques of Alzheimer's Disease (AD) result from ancient mechanisms in wound-healing and inflammatory processes that preceded the evolution of the inducible combinatorial immune responses characteristic of jawed vertebrates. AD plaques are unlike active plaques in MS, because antibodies, T-cells and, B cells are not conspicuous components of senile plaques or other loci of degeneration. However, senile plaques contain amyloids and other inflammatory proteins of ancient origin that appear to be made by local brain cells, including neurons, astrocytes, and microglia. We describe a highly conserved 16-mer found in pentrakins from mammals and from the horseshoe crab. The senile plaque thus provides a novel opportunity to study primitive features of complement-mediated inflammatory responses in the absence of immunoglobulins.
Alzheimer Disease↗
The evolution of ovarian oocyte decline with aging and possible relationships to Down syndrome and Alzheimer disease.
Evolutionary aspects of menopause are considered from several perspectives. First, the programmed exhaustion of ovarian oocytes appears to be a general trait of mammals that is not as widely found in other vertebrates. Second, studies on mice suggest that the maternal age effect that accelerates the incidence of Down syndrome is due not to age per se but to dwindling ovarian oocyte pools. Because Down syndrome inevitably leads to Alzheimer-type neuropathology, there is reason to consider hormonal intervention strategies to reduce the risk of Down syndrome. Third, estrogens may be a protective factor in Alzheimer disease, which is another link to menopause and another rationale for special hormonal interventions.
Aging↗
Inflammation and Alzheimer's disease.
Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
Alzheimer Disease↗
Rat 'DI 10' on the long road from diabetes insipidus to Alzheimer disease.
Explore the source record for details and available documents.
Alzheimer Disease↗
The glucocorticoid paradox of caloric restriction in slowing brain aging.
Glucocorticoids have a bimodal effect on cognition, hippocampal pyramidal neurons and long-term potentiation (LTP). Transient increases in glucocorticoids improve performance at spatial memory tasks and facilitate synaptic efficacy, depending on the context. On the other hand, long-term elevations of glucocorticoids are associated with decreased cognitive performance, attenuated synaptic efficacy and neuronal atrophy. Elevation of glucocorticoids during aging is also associated with mild cognitive impairment and hippocampal atrophy. Caloric restriction (CR), a dietary manipulation which extends life-span in rodents, also increases free plasma corticosterone. Recent data suggests that CR attenuates many brain aging changes and increases resistance of neurons to toxins and injury. Thus, a paradox may be considered: if CR causes chronic elevation of glucocorticoids, and if glucocorticoids can increase the risk of neurodegeneration, how can CR be neuroprotective. We suggest that the neuroprotective effects of CR outweigh the deleterious effects of glucocorticoids. The neuroprotective effects of CR that are discussed here include decreased plasma glucose, attenuated free radical generation, alterations of the vasculature, increased expression of heat shock proteins and neurotrophic factors, and attenuation of age-related glial activation.
Aged↗
Life-long dietary restriction attenuates age-related increases in hippocampal glial fibrillary acidic protein mRNA.
The expression of astrocyte-specific glial fibrillary acidic protein increases after experimental lesions and is elevated throughout the brain in aged rodents and primates. Clusterin (ApoJ) expression increases in astrocytes and microglia after lesions, but changes during aging have not been reported. Dietary restriction (DR) delays the onset and progression of many age-related physiological deficits in rodents. This study showed that the age-related increase in glial fibrillary acidic protein mRNA in the hippocampus was attenuated in 24-month-old male Fischer 344 rats subjected to a 50% DR beginning at 6 weeks of age. ApoJ mRNA expression in astrocytes was unchanged by DR. These results demonstrate that DR can delay neurodegeneration in aged rats as assessed by a marker of reactive astrogliosis.
Aging↗
Age-related activation of microglia and astrocytes: in vitro studies show persistent phenotypes of aging, increased proliferation, and resistance to down-regulation.
Astrocytes and microglia from cerebral cortex of 3-, 6-, 12-, and 24-month-old F344 male rat donors showed progressively greater proliferation during primary culture. Microglia from aging donor brains exhibited an amoeboid-like morphology and express antigens characteristic of an activated state (e.g., major histocompatibility complex class II). Moreover, microglia from aging donors were less sensitive to several types of regulators. Granulocyte-macrophage colony stimulating factor stimulated proliferation in microglia from young, but not aging brains. Transforming growth factor (TGF)-beta1 inhibited astrocytic and microglial proliferation in cultures from young, but not aging donors. Similarly, the inhibition of lipopolysaccharide-induced NO production by TGF-beta1 in microglia was impaired in cultures from 12-month (middle-age) brains. Another aging change detected by middle age, increased glial fibrillary acidic protein (GFAP) expression, also persisted in astrocytes from 12- to 24-month-old brains, as evaluated by increased activity of a 5'-upstream GFAP promoter construct. Thus, both microglia and astrocytes originated from aging cerebral cortex maintain in vitro at least some of the activated phenotypes of aging glia that are observed in vivo. This new in vitro cell model may allow efficient analysis of glial age changes.
Aging↗
Infrastructure for research on aging rodents: need for regional facilities to support transgenic studies on aging.
I propose that North American investigators who depend largely on individual external grants would benefit from the creation of regional facilities designed to support studies of aging in transgenic models. In general, academic institutions cannot achieve the most cost effectiveness because their facilities are not designed for industrial-scale cost efficiencies. Regional facilities would also increase the reproducibility of experiments. Transgenic studies of prospective genes that modify the risk of Alzheimer and other outcomes of aging could be carried out under standard conditions of nutrition and caging density, which can influence brain structure and behavior. The regional labs should have a strong Pathology Core, which would go far beyond the resources usually available to academic researchers. A national system of regional facilities with Core labs for characterizing genetics, hormones, and pathology would greatly accelerate progress.
Aging↗
The evolution of Alzheimer disease, the reproductive schedule, and apoE isoforms.
Alzheimer disease (AD)-like neuropathology increases progressively during aging in most primates, and, in some species, is concurrent with reproductive decline in females and cognitive impairments. We consider how the schedule of AD may have evolved in early humans in relation to the apolipoprotein E (apoE) allele system, which is not found in other primates, and to the increasing duration of postnatal care. The delay of independence and the increasing length of maturation required that the schedule of AD-like neurodegeneration be slowed, otherwise parental caregivers would already have become impaired. We hypothesize that the uniquely human apoE epsilon3 allele evolved from the epsilon4 of primate ancestors during human evolution in relation to the rapid increases of brain size and the emergence of grandmothering. In discussing theses possibilities, we review the diverse bioactivities of apoE, which include involvement in hormone systems. The evolution of menopause is also considered in relation to the protective effect of estrogen on AD.
Aging↗
Alex Comfort: intellectual eminence in science and humanism.
Explore the source record for details and available documents.
England↗
Aging and responses to toxins in female reproductive functions.
Reproductive senescence in laboratory rodents has been well characterized using vaginal smear analysis, a relatively simple and inexpensive technique to monitor changes in estrous cyclicity. Although some differences exist, laboratory animal models are available to study most aspects of age-related changes in human reproductive physiology (4,13). Thus presumptive reproductive toxins can be tested on laboratory rodents using the qualitative and quantitative parameters for estrous cyclicity described here to assess damage. Before implementing such tests, however, certain limitations must be considered. Quantitative changes in estrous cycles, for example, cycle length distribution, which indicate more subtle impairments in reproductive function, require more refined data analysis. In particular, baseline data for at least one month is required before exposure to the presumptive toxin. In addition, the period of maximum cycling regularity is fairly short (three to four months duration) so long-term exposures to presumptive toxins would not be applicable. Longer term exposure (greater than or equal to six months) would be permissible if qualitative changes in cyclicity (i.e., acyclic vs. cyclic) were the dependent variable used to assess toxicity. Finally, if other parameters of reproductive function (e.g., fertility, litter size) are used to assess reproductive toxicity, we urge that cycling characteristics of the offspring be carefully monitored to assess possible cryptic damage to later neuroendocrine functions that occurred to the fetuses in utero.
Aging↗
Combined in situ hybridization and immunocytochemistry in the assay of pharmacological effects on tyrosine hydroxylase mRNA concentration.
An assay for tyrosine hydroxylase (TH) mRNA by in situ hybridization in combination with immunocytochemistry (ICC) for TH on the same section is described. The in situ hybridization protocol was optimized for [35S]cRNA (complementary RNA, i.e. anti-sense strand) probe concentration and time of hybridization. The specificity of hybridization was measured by several critera. The advantage of measuring grain density versus grains per cell is discussed for quantitation of in situ autoradiography. Finally, the reserpine-induced increase in adrenal TH mRNA was used to validate quantitative aspects of the in situ hybridization technique by comparison with blot hybridization. In contrast to the adrenal, reserpine did not increase TH mRNA in substantia nigra (s. nigra) neurons as measured by either technique.
Animals↗
Evidence for an interaction between apolipoprotein E genotype, gender, and Alzheimer disease.
Carriers of the apolipoprotein E (APOE) epsilon4 allele show significantly higher risk of Alzheimer disease (AD). The aim of this present study was to test the hypothesis that a significant interaction exists between APOE genotype and gender on AD. Interactions of epsilon4 by gender, although indicated in the literature, require further verification. A total of 195 past or current control or AD participants in an ongoing longitudinal study of aging and dementia were genotyped. All subjects were at least 60 years old; demented subjects met clinical or pathologic criteria for late-onset AD. Logistic regression analysis and proportional hazard models were used to evaluate joint effects of APOE and gender. A significant statistical interaction between APOE and gender was shown (p = 0.04) in logistic regression analysis. Women carrying one or more APOE-epsilon4 allele were more likely to develop AD [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 3.2-19. 1]. For men, the presence of the APOE-epsilon4 allele was not associated with a statistically significant increased risk (OR = 1.6, 95% CI = 0.5-5.3). The interaction term in the proportional hazards model neared (p = 0.07) statistical significance, and a similar but reduced gender effect was shown. The analysis suggests that the presence of one or more APOE-epsilon4 allele confers a substantially greater risk of AD to women than to men. These findings in part may account for reports of increased risk of AD faced by women.
Aged↗
Complement activation in very early Alzheimer disease.
The activation of the classical complement (C)-system in early-stage Alzheimer disease (AD) and nondemented aging was examined with immunohistochemistry in subjects assessed by the Clinical Dementia Rating (CDR). Activation (staining for C3 and C4 fragments) was found in all brains with amyloid deposits, including all nondemented (CDR 0) cases, with either small numbers of diffuse plaques or with sufficient plaques and tangles to indicate preclinical AD. Staining for C3 and C4 increased in parallel with plaque density in very mild to severe clinical AD. A subset of very mild AD (CDR 0.5) cases also showed C1q (on plaques) and C5b-9 (on neuritic plaques and tangles), whereas these C-fragments were consistently found in severe AD (CDR 3). Mirror section (split-face) analysis showed that C1q, C3, and apoJ (clusterin) occurred on the same plaques. However, C-system regulators CD59, CR1, DAF, and MCP were not detected on plaques or tangles at any stage, indicating that C-activation related to AD is incompletely controlled.
Aged↗