Chromosome aneuploidy in Alzheimer''s disease

We present cytogenetic findings in 9 patients with Alzheimer's disease (AD) and 35 normal age matched controls. The study was undertaken due to reports of increased aneuploidy in individuals with AD. Coded peripheral blood chromosome preparations were evaluated for aneuploidy; there were 4.5% hypomodal cells in AD patients compared with 5.5% in controls. There were no hypermodal cells in the AD group and only 0.7% among the controls. Statistical analyses of the results did not show any differences between AD patients and controls in these data. There was a statistically significant increase in the loss of C group chromosomes in the old controls which we attribute to ageing.     

An integrative hypothesis concerning the pathogenesis and progression of Alzheimer''s disease

Observations, in Alzheimer's disease, in the pattern of nerve cell damage and loss, the pathology, microchemistry and immunology of senile plaques and neurofibrillary tangles and alterations in blood vessels are drawn together into a hypothesis that attempts to explain the pathogenesis and progression of the disorder. At the heart of this hypothesis lies a defect in blood brain barrier function and/or structure within the cerebral cortex and this defect may be the cause of the cerebral vessel amyloidosis common in many patients with Alzheimer's disease. Age-related alterations in blood brain barrier allow for damage to nerve terminals and limited formation of senile plaques within cerebral cortex; neurofibrillary tangles are formed within cortical and subcortical nerve cells which project to or near damaged vessels/senile plaques. Uptake of “neurotoxin” at affected terminals and retrograde transport to perikarya causes neurofibrillary tangles to be formed; their accumulation leads to perikaryal changes culminating in cell death and loss. Loss of cells in cortically projecting areas of subcortex such as nucleus basalis, locus caeruleus and dorsal raphe, which terminate on cerebral vessels, causes further blood brain barrier dysfunction, new plaque formation and continued cell loss in cortex and subcortex. Once started, such a process could be self-perpetuating and the initial site of damage could lie within the amygdala/hippocampus with putative pathogenic agent accessing the brain via the olfactory pathways.     

Platelet Protein Kinase C levels in Alzheimer''s disease

Alzheimer's disease (AD) has been suggested to be a systemic disease, and signal transduction abnormalities have been reported in non-neuronal AD cells. We have previously quantified the protein kinase C (PKC) subtypes in AD and control brains using a two-site enzyme immunoassay (EIA), and have shown that type II PKC levels were significantly reduced in the temporal cortex of AD patients. In this study, we used this EIA to assess the platelet levels of type II PKC in age-matched groups of AD patients and normal controls. The cytosolic level of type II PKC was significantly higher in AD platelets than in control platelets but was unchanged in the membranous fraction. Platelet proteins showed no differences between the AD and control groups. Therefore, the type II PKC content of the cytosolic fraction was increased in AD platelets. These results suggest that type II PKC may be altered in both the brain and platelets of AD patients and support the hypothesis that AD is a systemic disease.     

Soluble and membrane-bound forms of brain acetylcholinesterase in Alzheimer''s disease

In order to determine the effect of Alzheimer's disease on the relative distribution of soluble and membrane-bound molecular forms of acetylcholinesterase (AChE) in the brain, postmortem samples (delay interval less than 12 h) were obtained from parietal cortex (Brodmann area 40) and hippocampus as well as the areas containing their respective projection nuclei, i.e., substantia innominata and septal nucleus, in 9 patients with Alzheimer's disease (AD) and 4 normal controls. The monomer (G₁), dimer (G₂), and tetramer (G₄) forms of AChE were examined. In AD compared to controls, significant changes occurred in area 40 and hippocampus but not in the areas containing projection nuclei, and included loss of mean total AChE activity, decrease in the relative percentage of membrane-bound G₄, and increase in the relative percentage of soluble G₁---G₂. Percent of soluble G₄ was unaffected in AD brain. In area 40 but not hippocampus a large increase in percent membrane-bound G₁-G₂ occurred. Thus, these results emphasize that the selective decrease in membrane-bound G₄ accounts for the decrease in total G₄ activity in AD brain.     

Gustatory and olfactory dysfunction in dementia: Not specific to Alzheimer''s disease

Significant losses in the ability to detect the taste of glutamic acid and to recognize odorants were found in demented patients when compared with age-matched controls. These losses were not specific to patients with Alzheimer's disease (AD) but were also found in demented patients without AD. Detection thresholds for bitter-tasting quinine HCl were not higher in demented patients than in age-matched controls but were higher than thresholds in young subjects. These data suggest that losses in taste in demented patients may vary with the chemical structure of the tastant. The degree of loss in the ability to recognize odorants was greater in patients with a family history of senile dementia.     

Distribution of fibroblast growth factor receptor-1 (FGFR-1) and FGFR-3 in the hippocampus of patients with Alzheimer''s disease

To learn about the localization of fibroblast growth factor (FGF) ligands in normal and pathologic brains, fibroblast growth factor receptor-1 (FGFR-1; Flg) and FGFR-3 immunoreactivities were examined in the hippocampus of patients with Alzheimer's disease and age-matched controls. Flg immunoreactivity was found in practically all neurons of the hippocampus and dentate gyrus in control and Alzheimer's disease cases. In patients with Alzheimer's disease, Flg immunoreactivity was present in tangle-bearing and non-tangle-bearing neurons, as well as in neurons with granulovacuolar degeneration, but not in ghost tangles. Aberrant neurites of senile plaques were negative. FGFR-3 immunoreactivity was found in reactive glial cells, most of them astrocytes, including those in the vicinity of senile plaques.     

Absence of aluminium in neurofibrillary tangles in Alzheimer''s disease

Using the new technique of nuclear microscopy, aluminium is not detected in pyramidal neurons in brain tissue from Alzheimer's disease (AD) patients. The analytical technique of nuclear microscopy can simultaneously image and analyse features in unstained and untreated tissue sections. In tissue which had been previously subjected to conventional procedures such as fixation and osmication, aluminium was observed in both neurons and surrounding tissue. This result shows that the analysis of tissue prepared using conventional chemical techniques may produce contamination or elemental redistribution, and supports our previous investigations which implied that aluminium is not involved in the aetiology of AD. In addition, significant increases in iron, phosphorus and sulphur concentrations were noted between neurons from Alzheimer tissue and neurons from age-matched controls, and between the supporting Alzheimer tissue and supporting control tissue, implying an overall increase in these elements. No significant increase in calcium was observed between neurons from Alzheimer tissue and neurons from age-matched controls.     

神经生长因子偶联物对老年性痴呆动物模型的保护作用

目的　探讨神经生长因子偶联物 (NGF -Tf)对老年性痴呆 (AD)大鼠的影响 .方法　以手术切断大鼠双侧隔 -海马胆碱能通路的方法建立AD动物模型 ,每天从大鼠尾静脉注射NGF -Tf .通过水迷路试验观察大鼠的记忆和方向辨别能力 ;对海马和隔区行神经组织学检查 ;应用酶组织化学技术显示相应区域的ChAT ,采用计算机病理图像分析系统测定酶活性以判断其胆碱能功能状态 .结果　水迷路试验中 ,NGF -Tf组在 10s内抵达平台的正确反应平均数提高 (p <0 .0 5 ) .光镜下 ,NGF -Tf组隔区仅见轻微萎缩性改变 ,而模型组隔区萎缩性改变较明显 ,表现为神经元数目明显减少 ,细胞轮廓不清 ,有胶质细胞增生 ;正常对照组、NGF -Tf组和模型组的海马区未见明显病理性改变 .ChAT染色统计结果显示 ,正常对照组、NGF -Tf组大鼠的海马区及隔区IOD值与模型组比较 ,均有显著性差异 (p <0 .0 1) .结论　NGF -Tf能穿透血脑屏障 ,有效防止模拟AD病变的大鼠的基底前脑胆碱能神经元的变性和死亡 ,改善其记忆和方向辨别能力 ,促进其胆碱能神经元的功能恢复     

Proteomics in animal models of Alzheimer's and Parkinson's diseases

The risk of developing neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) increases with age. AD and PD are the two most common neurodegenerative diseases that currently affect millions of persons within the United States population. While many clues about the mechanisms of these disorders have been uncovered, to date, the molecular mechanisms associated with the cause of these diseases are not completely understood. Furthermore, there are no available cures or preventive treatments for either disorder. Animal models of AD and PD, though not perfect, offer a means to gain knowledge of the basic biochemistry associated with these disorders and with drug efficacy. The field of proteomics which focuses on identifying the dynamic nature of the protein content expressed within a particular cell, tissue, or organism, has provided many insights into these disturbing disorders. Proteomic studies have revealed many pathways that are associated with disease pathogenesis and that may lead to the development of potential therapeutic targets. This review provides a discussion of key findings from AD and PD proteomics-based studies in various animal models of disease.     

Increased proteolytic activity in lymphocytes from patients with early onset Alzheimer''s disease

The levels of calpains (m-calpain and μ-calpain) in peripheral blood lymphocytes from patients with Alzheimer's disease were determined via Western blotting. The Ca-dependent proteolytic activity and the calpastatin activity were estimated using incubation with exogenous substrate. Evidence was obtained for an increased Ca-dependent proteolytic activity in lymphocytes from patients with early onset Alzheimer's disease. There was also an increased level of membrane-bound μ-calpain in this group of patients. The observed changes may be caused by a general dysregulation of Ca homeostasis in peripheral cells of early onset Alzheimer victims.     

The role of cell cycle-mediated events in Alzheimer''s disease

The mechanism(s) underlying selective neuronal death in Alzheimer's disease remain unresolved. However, recently, we and others showed that susceptible hippocampal neurones in Alzheimer's disease express markers common to cells in various phases of the cell cycle. Since neuronal maturation is associated with effective escape from the cell division cycle, emergence out of quiescence may be deleterious. Here, we review a number of current findings indicating that disregulated ectopic re-activation of cell cycle-mediated events, akin to neoplasia, represent an important early pathway associated with neuronal death and, more importantly, one that involves virtually the entire spectrum of the pathological events described in Alzheimer's disease.     

Oxidative stress and overexpression of manganese superoxide dismutase in patients with Alzheimer''s disease

Substantial evidence supports the hypothesis that oxygen free radicals are involved in various neurodegenerative disorders. To assess the presence of oxidative stress in Alzheimer's disease (AD) we examined the activity of the enzyme copper-zinc superoxide dismutase (CuZnSOD) in red blood cells, the levels of the mitochondrial inducible enzyme manganese superoxide dismutase (MnSOD) mRNA in lymphocytes, and the total radical-trapping antioxidant capacity (TRAP) in plasma of AD patients and in a group of age-matched non-demented controls. We found that CuZnSOD activity (P<0.01 vs. controls) was significantly increased as well as the MnSOD mRNA levels while the total antioxidant status (P<0.001 vs. controls) was decreased in AD patients. These findings support the role of oxidative alterations in the pathogenetic mechanism underlying AD neurodegeneration.     

Advantages and limitations of mouse models to deplete dendritic cells

Dendritic cells (DCs) play a key role in regulating innate and adaptive immunity. Our understanding of DC biology has benefited from studies in CD11c.DTR and CD11c.DOG mouse models that use the CD11c promoter to express a diphtheria toxin (DT) receptor transgene to inducibly deplete CD11c⁺ cells. Other models to inducibly deplete specific DC subsets upon administration of DT have also been generated. However, most models suffer from limitations such as depletion of additional cell types or the requirement to be used as radiation chimeras. Moreover, CD11c.DTR and CD11c.DOG mice have recently been reported to display neutrophilia and monocytosis upon DT injection. We discuss here some of the limitations that should be taken into consideration when interpreting results obtained with mouse models of DC ablation.     

Complement mRNA in the mammalian brain: Responses to Alzheimer''s disease and experimental brain lesioning

This study describes evidence in the adult human and rat brain for mRNA's that encode two complement (C) proteins, C1qB and C4. C proteins are important effectors of humoral immunity and inflammation in peripheral tissues but have not been considered as normally present in brain. Previous immunocytochemical studies showed that C proteins are associated with plaques, tangles, and dystrophic neurites in Alzheimer's disease (AD), but their source is unknown. Combined immunocytochemistry and in situ hybridization techniques show C4 mRNA in pyramidal neurons and C1qB mRNA in microglia. Primary rat neuron cultures also show C1qB mRNA.

In the cortex from AD brains, there were two- to threefold increases of C1qB mRNA and C4 mRNA, and increased C1qB mRNA prevalence was in part associated with microglia. As a model for AD, we examined entorhinal cortex perforant path transection in the rat brain, which caused rapid increases of C1qB mRNA in the ipsilateral, but not contralateral, hippocampus and entorhinal cortex. The role of brain-derived acute and chronic C induction during AD and experimental lesions can now be considered in relation to functions of C proteins that pertain to cell degeneration and/or cell preservation and synaptic plasticity.     

Confabulations in remembering past and planning future are associated with psychiatric symptoms in Alzheimer''s disease

Psychiatric symptoms such as delusions and aggression are frequently observed in patients with Alzheimer's disease (AD), but few studies examined the association of these symptoms with confabulations. We studied 32 AD patients and 10 age- and education-matched healthy older adults. The AD patients were divided into delusion/aggression and non-delusion/non-aggression groups based on their behavioral pathology in AD frequency-weighted severity scale score. Confabulations were assessed using questions about temporality (personal past, orientation, and future planning), and cognitive functions were determined using the mini-mental state examination and the cognitive abilities screening instrument. The AD patients showed confabulations on all types of questions, and their confabulation scores for the past and future were strongly correlated. Cognitive functions were not significantly correlated with confabulation scores for any type of questions. The delusion/aggression group had significantly more confabulations on past and future questions compared to the non-delusion/non-aggression group. These findings suggested that confabulations in remembering the past and planning the future were affected by psychiatric symptoms such as delusion and aggression.     

Stem cell therapy for Alzheimer's disease: An overview of experimental models and reality

Alzheimer's disease (AD) is a neurodegenerative disorder. The pathology of AD is characterized by extracellular amyloid beta (Aβ) plaques, neurofibrillary tangles com-posed of hyperphosphorylated tau, neuronal death, synapse loss, and brain atrophy. Many therapies have been tested to improve or at least effectively modify the course of AD. Meaningful data indicate that the transplantation of stem cells can alleviate neuropathology and significantly ameliorate cognitive deficits in animal models with Alzheimer's disease. Transplanted stem cells have shown their inherent advantages in improving cognitive impairment and memory dysfunction, although certain weak-nesses or limitations need to be overcome. This review recapitulates rodent models for AD, the therapeutic efficacy of stem cells, influencing factors, and the underlying mechanisms behind these changes. Stem cell therapy provides perspective and chal-lenges for its clinical application in the future.     

Animal models of cognitive dysfunction

The increased life expectancy in industrialised countries in the last half century has also brought to a greater incidence of neurological disorders, including neurodegenerative diseases and developing in a rather long time. In this respect, Alzheimer's disease (AD), for the large incidence, and the dramatic loss of autonomy caused by its cognitive and behavioural symptoms represents one of the main challenges of modern medicine. Although AD is a typical human disease and probably includes several nosographic entities, the use of animal models may contribute to understand specific aspects of pathophysiology of the disease. The most widely used animal models are rodents and non-human primates. In this review different animal models characterised by impaired cognitive functions are analysed. None of the models available mimics exactly cognitive, behavioural, biochemical and histopathological abnormalities observed in neurological disorders characterised by cognitive impairment. However, partial reproduction of neuropathology and/or cognitive deficits of Alzheimer's disease (AD), vascular dementia and dementia occurring in Huntington's and Parkinson's diseases, or in other neurodegenerative disorders may represent a basis for understanding pathophysiological traits of these diseases and for contributing to their treatments.     

Identification of a novel mutation (Leu282Arg) of the human presenilin 1 gene in Alzheimer''s disease

Many different mutations, causative of Alzheimer's disease, have been found in the presenilin-1 gene (PS-1). We have developed a screening method based on denaturing gradient gel electrophoresis (DGGE), which allows the mutational analysis of the whole exon 9 of PS-1. Upon the screening of a Spanish sample of early onset familial Alzheimer disease cases, we have found a novel mutation in the PS-1 gene. The mutation (a T to G transition) results in a change of the amino acid at position 282 of the presenilin protein from leucine to arginine. This mutation is located in the hydrophobic domain number 7 (exon 9) close to the site of physiological cleavage processing. The average of onset of the affected members of this family is 43±5 years, and the average age of exitus of affected members is 56±3 years. The possibility to determine the specific pathologic mechanisms of this mutation is now open.     

Animal models in the study of Alzheimer's disease and Parkinson's disease: A historical perspective

Alzheimer's disease and Parkinson's disease are two of the most prevalent and disa-bling neurodegenerative diseases globally. Both are proteinopathic conditions and while occasionally inherited, are largely sporadic in nature. Although the advances in our understanding of the two have been significant, they are far from complete and neither diagnosis nor the current practices in treatment and rehabilitation is ad-equately helpful. Animal models have historically found application as testing beds for novel therapeutics and continue to be valuable aids in pharmacological research. This review chronicles the development of those models in the context of Alzheimer's and Parkinson's disease, and highlights the shifting paradigms in studying two human- specific conditions in non- human organisms.     

Binding of platelet-activating factor to platelets of Alzheimer''s disease and multiinfarct Dementia patients

The binding of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor, PAF) to platelets was studied in 22 patients with probable Alzheimer's disease (AD), 11 with multi-infarct dementia (MID), 22 age-matched normal old controls, and 20 young subjects. The results showed a significantly lower degree of PAF binding to platelets of AD and MID patients than in those of the old controls and young subjects (133.3 ± 8.5, and 123.4 ± 16.5 vs. 202.3 ± 11.6 and 206.7 ± 17.3 receptors/cell, respectively; p < 0.01). These differences were due to reduced B_max, while K_d remained unchanged. No significant difference was observed between the PAF binding to platelets of AD and MID patients nor between that of old and young controls. No correlation was found between age and binding in the various elderly groups. However, a significant correlation was found between PAF binding and degree of cognitive impairment in the AD patients. This is the first evidence to support a possible involvement of PAF in dementing disorders.