Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer's disease

Alzheimer's disease (AD) is characterized pathologically by plaques, tangles, and cell and synapse loss. As glutamate is the principle excitatory neurotransmitter of the CNS, the glutamatergic system may play an important role in AD. An essential step in glutamate neurotransmission is the concentration of glutamate into synaptic vesicles before release from the presynaptic terminal. Recently a group of proteins responsible for uptake has been identified - the vesicular glutamate transporters (VGLUTs). The generation of antibodies has facilitated the study of glutamatergic neurones. Here, we used antibodies to the VGLUTs together with immunohistochemistry and western blotting to investigate the status of glutamatergic neurones in temporal, parietal and occipital cortices of patients with AD; these regions were chosen to represent severely, moderately and mildly affected regions at the end stage of the disease. There was no change in expression of the synaptic markers in relation to total protein in the temporal cortex, but a significant reduction in synaptophysin and VGLUT1 was found in both the parietal and occipital cortices. These changes were found to relate to the number of tangles in the temporal cortex. There were no correlations with either mental test score or behaviour syndromes, with the exception of depression.     

The amyloid hypothesis for Alzheimer's disease: a critical reappraisal

The amyloid hypothesis has been the basis for most work on the pathogenesis of Alzheimer's disease. Recent clinical trials based on this hypothesis have been inconclusive. In this article I review the current status of the hypothesis and suggest that a major scientific need is to understand the normal function of amyloid-β precursor protein (APP) and think how this may relate to the cell death in the disease process.     

Trace elements in Alzheimer's disease pituitary glands

Levels of mercury (Hg), selenium (Se), iron (Fe), rubidium (Rb), and zinc (Zn) were measured in the pituitary gland to assess the possibility of a potential difference in the environmental Hg exposure of Alzheimer's disease (AD) patients and control subjects and levels of other elements of interest in AD. The pituitary gland has been established as a good predictor of environmental Hg exposure. Neutron activation analysis was utilized to determine levels of these elements in pituitary glands of 43 AD subjects and 15 control subjects. No significant differences were observed between the AD and control means for these five elements. The sole significant Pearson's correlation involving Hg was the established correlation with Se, indicative of the detoxification of Hg. The absence of a statistical difference between AD and control pituitary gland Hg levels suggests AD patients do not have an excessive environmental exposure to Hg compared to controls.     

Possible factors in the etiology of Alzheimer's disease

Inherited cases of Alzheimer's disease (AD) comprise only a very small proportion of the total. The remainder are of unknown etiopathogenesis, but they are very probably multifactorial in origin. This article describes studies on four possible factors: aluminum; viruses—in particular, herpes simplex type I virus (HSV1); defective DNA repair; and head trauma. Specific problems associated with aluminum, such as inadvertent contamination and its insolubility, have led to some controversy over its usage. Nonetheless, the effects of aluminum on animals and neuronal cells in culture have been studied intensively. Changes in protein structure and location in the cell are described, including the finding in this laboratory of a change in τ resembling that in AD neurofibrillary tangles, and also the lack of appreciable binding of aluminum to DNA. As for HSV1, there has previously been uncertainty about whether HSV1 DNA is present in human brain. Work in this laboratory using polymerase chain reaction has shown that HSV1 DNA is present in many normal aged brains and AD brains, but is absent in brains from younger people. Studies on DNA damage and repair in AD and normal cells are described, and finally, the possible involvement of head trauma is discussed.     

Binding of zinc(II) and copper(II) to the full-length Alzheimer's amyloid-beta peptide

There is evidence that binding of metal ions like Zn2+ and Cu2+ to amyloid beta-peptides (Abeta) may contribute to the pathogenesis of Alzheimer's disease. Cu2+ and Zn2+ form complexes with Abeta peptides in vitro; however, the published metal-binding affinities of Abeta vary in an enormously large range. We studied the interactions of Cu2+ and Zn2+ with monomeric Abeta(40) under different conditions using intrinsic Abeta fluorescence and metal-selective fluorescent dyes. We showed that Cu(2+) forms a stable and soluble 1 : 1 complex with Abeta(40), however, buffer compounds act as competitive copper-binding ligands and affect the apparent K(D). Buffer-independent conditional K(D) for Cu(II)-Abeta(40) complex at pH 7.4 is equal to 0.035 micromol/L. Interaction of Abeta(40) with Zn2+ is more complicated as partial aggregation of the peptide occurs during zinc titration experiment and in the same time period (within 30 min) the initial Zn-Abeta(40) complex (K(D) = 60 micromol/L) undergoes a transition to a more tight complex with K(D) approximately 2 micromol/L. Competition of Abeta(40) with ion-selective fluorescent dyes Phen Green and Zincon showed that the K(D) values determined from intrinsic fluorescence of Abeta correspond to the binding of the first Cu2+ and Zn2+ ions to the peptide with the highest affinity. Interaction of both Zn2+ and Cu2+ ions with Abeta peptides may occur in brain areas affected by Alzheimer's disease and Zn2+-induced transition in the peptide structure might contribute to amyloid plaque formation.     

Constructing Alzheimer's: Narratives of Lost Identities,Confusion and Loneliness in Old Age

This paper is a qualitative study based on retrospective, unstructured, qualitative interviews with Mrs. Jones and other African-American, Chinese-American, Irish-American and Latino family caregivers in the Boston area. A narrative approach is used to show how family caregivers draw on their cultural and personal resources to create stories about the nature and meaning of illness and to ask how ethnic identity may influence the kinds of stories family caregivers tell. Three different story types are identified and described, each with a distinctive configuration of illness meanings and overarching theme, or storyline: a subset of African-American, Irish-American, and Chinese-American caregivers told us stories about Alzheimer's as a disease that erodes the core identity of a loved one and deteriorates their minds; a subset of Chinese caregivers narrated stories that emphasized how families managed confusion and disabilities, changes ultimately construed as an expected part of growing old; a subset of Puerto Rican and Dominican families, while using the biomedical label of Alzheimer's disease or dementia, placed the elder's illness in stories about tragic losses, loneliness, and family responsibility. To construct their stories, caregivers drew upon both biomedical explanations and other cultural meanings of behavioral and cognitive changes in old age. Their stories challenge us to move beyond the sharp contrast between ethnic minority and non-ethnic minority views of dementia-related changes, to local clinics and hospitals as sites where biomedical knowledge is interpreted, communicated, discussed, and adapted to the perspectives and lived realities of families.     

Zinc status does not affect aluminum deposition in tissues of rats

To examine whether zinc deficiency would increase the toxicity of dietary aluminum, weanling, male Sprague-Dawley rats were fed purified diets containing either 2 or 30 mg Zn/kg diet, with or without 500 mg Al/kg diet for 28 d. Individually pair-fed rats were fed the 30 mg Zn/kg diet with or without added aluminum to control for inanition secondary to zinc deficiency. Rats fed the 2 μg Zn/kg diet showed evidence of zinc deficiency, including anorexia, growth retardation, and depressed concentrations of zinc in tibias and livers. Zinc deficiency did not significantly increase the concentrations of aluminum in the tibias, livers, kidneys, or regions of the brain examined (cerebrum, cerebellum, midbrain, and hippocampus). Inclusion of aluminum in the diet did not alter aluminum concentrations in the various tissues. Under the conditions of this study, zinc deficiency did not result in greater sensitivity to dietary aluminum exposure.     

Radioiodinated clioquinol as a biomarker for beta-amyloid: Zn complexes in Alzheimer's disease

Neocortical beta-amyloid (Abeta) aggregates in Alzheimer's disease (AD) are enriched in transition metals that mediate assembly. Clioquinol (CQ) targets metal interaction with Abeta and inhibits amyloid pathology in transgenic mice. Here, we investigated the binding properties of radioiodinated CQ ([(125)I]CQ) to different in vitro and in vivo Alzheimer models. We observed saturable binding of [(125)I]CQ to synthetic Abeta precipitated by Zn(2+) (K(d)=0.45 and 1.40 nm for Abeta(1-42) and Abeta(1-40), respectively), which was fully displaced by free Zn(2+), Cu(2+), the chelator DTPA (diethylene triamine pentaacetic acid) and partially by Congo red. Sucrose density gradient of post-mortem AD brain indicated that [(125)I]CQ concentrated in a fraction enriched for both Abeta and Zn, which was modulated by exogenous addition of Zn(2+) or DTPA. APP transgenic (Tg2576) mice injected with [(125)I]CQ exhibited higher brain retention of tracer compared to non-Tg mice. Autoradiography of brain sections of these animals confirmed selective [(125)I]CQ enrichment in the neocortex. Histologically, both thioflavine-S (ThS)-positive and negative structures were labeled by [(125)I]CQ. A pilot SPECT study of [(123)I]CQ showed limited uptake of the tracer into the brain, which did however, appear to be more rapid in AD patients compared to age-matched controls. These data support metallated Abeta species as the neuropharmacological target of CQ and indicate that this drug class may have potential as in vivo imaging agents for Alzheimer neuropathology.     

The clinical syndrome of Alzheimer's disease: aspects particularly relevant to clinical trials

This paper describes the natural history of the clinical syndrome of Alzheimer's disease (AD) including the cognitive deficit, the neuropsychiatric symptoms, impact on daily functioning, risk factors, medical complications and impact on the use of health-care resources. The clinical presentation of the disease varies greatly from the prodrome through end stage; instruments used to quantify the severity of each aspect of the disease have been developed and are described along with their use in clinical drug trials. Drug treatments for AD are usually developed by first showing a positive effect on the cognitive deficit, with later studies investigating drug effects on other clinical aspects of the disease.     

Alzheimer's disease cerebrospinal fluid antibodies display selectivity for microglia

Previous investigations demonstrated that the cerebrospinal fluid (CSF) from Alzheimer's disease (AD) patients contains antibodies that recognize specific neuronal populations in the adult rat central nervous system (CNS). These findings suggest a pathogenic role for immunological aberrations in this disorder. To determine if antibodies may provide a means to differentially diagnose the dementias, CSF from a diversified dementia population was screened against the developing rat CNS and a cell culture system. Markings produced by AD CSF were distinctly different from those of vascular dementias (VAD) against the developing rat CNS. More importantly, some AD CSF recognized amoeboid microglia. The recognition of amoeboid microglia by antibodies in AD CSF is particularly interesting since these cells proliferate in response to nervous system disease and also engulf debris. A cell culture technique was developed to allow the rapid screening of CSF antibodies. Patient CSF produced five different types of markings in the cell culture: microglia, glioblasts, fibers, nonspecific, or negative. Correlations with these structures and the diagnosis of four different dementia populations revealed that, in comparison to the other groups, AD CSF displayed remarkable selectivity toward microglial cells. Cortical biopsies from patients suspected to have AD were incubated with the patient's own CSF and that of confirmed AD patients. Both CSF samples recognized microglial cells in the patient's cortical biopsy. The same CSF samples incubated against normal human cortical autopsy or a biopsy from a 3-mo-old child displayed negative immunoreactivity. These three approaches suggest that the presence of CSF microglial antibodies may be a means to distinguish AD patients from other dementias. The results add further support to the widely growing concept that inflammation and similar immune mechanisms may contribute to AD pathogenesis.     

Progestins and estrogens and Alzheimer's disease

Sex-specific incidence rates for Alzheimer's disease (AD) are higher in women than men. Many fundamental researches and some clinical investigations have reported therapeutic and preventive effects of estrogens on AD. But WHIMS [S.A. Shumaker, C. Legault, S.R. Rapp, L. Thal, R.B. Wallace, J.K. Ockene, S.L. Hendrix, B.N. Jones IIIrd, A.R. Assaf, R.D. Jackson, J.M. Kotchen, S. Wabertheil-Smoller, J. Wactawsk-Wende, WHIMS investigators, Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The women's health initiative memory study: a randomized controlled trial, JAMA 289 (2003) 2651–2662], which used daily continuous hormone replacement therapy (HRT), reported that the hazard ratio of the HRT for probable dementia was 2.05.

Effect of progestins, and continuous (not cyclically) HRT, even only with estrogen should be reconsidered.

In our clinical study, conjugated equine estrogen (CEE) alone showed good changes of psychiatric tests for AD on the 3rd week, but addition of medroxyprogesterone acetate (MPA) or norethindrone since 4th week suppressed these tests. Using human umbilical vein epithelial cell (HUVEC), levonorgestrel (LNG), norethindrone acetate (NETA), MPA increased intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion melocule-1 (VCAM-1) and E-secretin but dienogest (DNG) showed no effect. In vitro flow system, estradiol (E₂), suppressed adhesion of white cell, but LNG, NETA, MPA increased the adhesions. DNG showed less effect.

Non-feminizing estrogen J 861, which has Δ8,9 double bond and straight in its structure and has less effect on sexual organs. J 861 has shown ameliorative effects on central nervous system (CNS) (increasing of cholineacetyltransferase immunoreactive cells in substantia innominata (SI), etc.) like E₂.

More investigations about progestins and estrogens and AD should be done.     

Alzheimer's disease and estrogen

The preventive effect of estrogen on Alzheimer's disease (AD) has become clear with epidemiological data. Therapeutic effects of estrogen have not yet been established. In this presentation, we report our new basic and clinical data. The estrogen receptor, (ER), and ERβ mRNA were investigated in rat brain. Estradiol-17β (E₂) treatment following OVX reduced the levels of ER mRNA in the hypothalamus. In the substantia innominata (SI), the number of choline acetyltransferase immunoreacive cells increased significantly in the estrogen treatment rat. The neurons in SI projecting to the forebrain cortex contained ER. Increasing amounts of intracellular calcium, peroxidation, and apoptosis with amyloid β were suppressed in neuronal cells from rat pheochromocytoma (PC12) cells with E₂. ER cDNA transfected PC 12 cells elaborated more neurite-like processes with E₂. In clinics, we are currently preparing vaginal progesterone tablets, which essentially may concentrate in the endometrium to prevent endometrial cancer, with few general circulation of progesterone inviting less depression. The therapeutic effects of cyclic estrogen, such as its preventive effect, are suggested in these studies, at least on mild AD.     

New therapeutic targets in Alzheimer's disease: brain deregulation of calcium and zinc

The molecular determinants of Alzheimer''s (AD) disease are still not completely known; however, in the past two decades, a large body of evidence has indicated that an important contributing factor for the disease is the development of an unbalanced homeostasis of two signaling cations: calcium (Ca²⁺) and zinc (Zn²⁺). Both ions serve a critical role in the physiological functioning of the central nervous system, but their brain deregulation promotes amyloid-β dysmetabolism as well as tau phosphorylation. AD is also characterized by an altered glutamatergic activation, and glutamate can promote both Ca²⁺ and Zn²⁺ dyshomeostasis. The two cations can operate synergistically to promote the generation of free radicals that further intracellular Ca²⁺ and Zn²⁺ rises and set the stage for a self-perpetuating harmful loop. These phenomena can be the initial steps in the pathogenic cascade leading to AD, therefore, therapeutic interventions aiming at preventing Ca²⁺ and Zn²⁺ dyshomeostasis may offer a great opportunity for disease-modifying strategies.     

Towards the prevention of potential aluminum toxic effects and an effective treatment for Alzheimer's disease

In 1991, treatment with low dose intramuscular desferrioxamine (DFO), a trivalent chelator that can remove excessive iron and/or aluminum from the body, was reported to slow the progression of Alzheimer's disease (AD) by a factor of two. Twenty years later this promising trial has not been followed up and why this treatment worked still is not clear. In this critical interdisciplinary review, we provide an overview of the complexities of AD and involvement of metal ions, and revisit the neglected DFO trial. We discuss research done by us and others that is helping to explain involvement of metal ion catalyzed production of reactive oxygen species in the pathogenesis of AD, and emerging strategies for inhibition of metal-ion toxicity. Highlighted are insights to be considered in the quests to prevent potentially toxic effects of aluminum toxicity and prevention and intervention in AD.     

Motor impairment in Alzheimer's disease and transgenic Alzheimer's disease mouse models

In this commentary, we accent the accumulating evidence for motor impairment as a common feature of early Alzheimer's disease (AD) pathology. In addition, we summarize the state of knowledge on this phenotype in experimental mouse models, expressing AD-associated genes like tau or amyloid precursor protein.     

Effects of dietary tin and aluminum on selenium utilization by adult males

The main purpose of these studies was to determine whether the amounts of tin and aluminum that can enter foods during processing and storage are sufficient to affect the utilization of selenium by human subjects. Two 40-day balance studies were conducted. The eight adult males who participated in the first study lost significantly more selenium in their feces when fed a test diet containing 50 mg tin daily than when fed the control diet containing 0.1 mg tin daily. During the first study subjects tended to excrete less selenium in the urine when fed the test diet rather than the control diet. In the second study, the dietary treatments (5 and 125 mg aluminum daily) had no effect on the excretion and apparent retention of selenium by eight adult males.     

Alzheimer's disease,oral function and nutritional status

Objectives: To study differences in nutritional, dental status and oral function between institutionalised patients with Alzheimer's disease and cognitively healthy elderly people living in the community. Design: Comparison was made between two groups, Alzheimer's disease sufferers and healthy controls, using established criteria for anthropometric, mental and dental state. Setting: An institution and residential area in Stockholm, Sweden. Subjects: Forty patients with Alzheimer's disease living in a nursing home and 40 age-and gender-matched control subjects living independently. Intervention: Dental status and anthropometric variables. Results: Overnutrition was less frequent among the demented than the controls and more demented were undernourished. Dental status was similar in the two groups with few edentulous subjects but only 2 of 7 edentulous subjects with Alzheimer's disease wore dentures. Having natural teeth and many functional oral zones is important for food consistency choice, but not for nutritional status. In the Alzheimer group, the stage of dementia has a strong association to the ability to eat unaided and an association with dental status. Conclusion: There are differences in nutritional status between Alzheimer's patients in institutions and cognitively healthy elderly living at home. The choice of food consistency is correlated to dental status but nutritional status is not shown to be influenced by dental status. However, the ability to eat unaided is strongly correlated to cognitive status.     

Alzheimer's disease,oral function and nutritional status

Objectives: To study differences in nutritional, dental status and oral function between institutionalised patients with Alzheimer's disease and cognitively healthy elderly people living in the community. Design: Comparison was made between two groups, Alzheimer's disease sufferers and healthy controls, using established criteria for anthropometric, mental and dental state. Setting: An institution and residential area in Stockholm, Sweden. Subjects: Forty patients with Alzheimer's disease living in a nursing home and 40 age-and gender-matched control subjects living independently. Intervention: Dental status and anthropometric variables. Results: Overnutrition was less frequent among the demented than the controls and more demented were undernourished. Dental status was similar in the two groups with few edentulous subjects but only 2 of 7 edentulous subjects with Alzheimer's disease wore dentures. Having natural teeth and many functional oral zones is important for food consistency choice, but not for nutritional status. In the Alzheimer group, the stage of dementia has a strong association to the ability to eat unaided and an association with dental status. Conclusion: There are differences in nutritional status between Alzheimer patients in institutions and cognitively healthy elderly living at home. The choice of food consistency is correlated to dental status but nutritional status is not shown to be influenced by dental status. However, the ability to eat unaided is strongly correlated to cognitive status.     

阿茨海默氏病研究

阿茨海默氏病（Alzheimer‘s disease,AD）受到科学界的广泛关注。已发现的AD相关基因的突变,只能解释某有族性病例,而至少60％的AD患者没有家族史,对这些散发性AD的病理,van Leeuwen等做了有意义 探索,他们的实验证明,AD脑部存在由于GA缺失造成移码突变的β淀粉样蛋白前体和泛素－B,并推测这种移码突变是AD病理的重要起妈因子。该实验开辟了从蛋白合成错误的角度研究AD的新视点,并为RNA编辑提供了新的类型。     

Changes in Chromatin Structure Associated with Alzheimer's Disease

Abstract— The enzyme micrococcal nuclease was used to examine the accessibility of chromatin extracted from brains of 13 patients with senile and presenile dementia of the Alzheimer type. Compared with chromatin extracted from brains of 8 patients without neurological signs or brain pathology and brains of 7 patients with nonAlzheimer dementia, Alzheimer chromatin was less accessible to this enzyme-. Reduced accessibility was reflected by a reduced yield of mononucleosomes in comparison with dinucleosomes and larger oligomers. Both neuronal and glial chromatin were found to be similarly affected. The reduced yield of mononucleosomes from Alzheimer chromatin is not due to their increased breakdown, but is probably related to protein associated with the internucleosomal linker region that retards nuclease action. Dinucleosomes isolated from control and Alzheimer nuclease digests were examined for their protein complement. Three perchloric acid-soluble proteins situated in the histone HI region of sodium dodecyl sulfate (SDS) gels were present in elevated levels in Alzheimer dinucleosomes. These results represent the first example of altered chromosomal proteins associated with a diseased state of the brain.