Alzheimer's disease and Down's syndrome

The neuropathology of Down's syndrome at middle age is compared with that of Alzheimer's disease at that age, through a review of the published literature and from the author's personal observations. The pathological changes of Down's syndrome at middle age, i.e. the form and distribution of senile plaques and neurofibrillary tangles, and the pattern of involvement (atrophy) of neuronal systems are qualitatively the same as those of Alzheimer's disease at that age. Quantitative differences do occur and these may relate to biological or sociological variations inherent to the two parent populations. It is concluded that, in pathological terms, patients with Down's syndrome at middle age do indeed have Alzheimer's disease. Some ways in which a study of patients with Down's syndrome can give insight into the nature and development of the pathological changes of Alzheimer's disease are put forward and discussed.     

Down's syndrome and Alzheimer's disease: a review

Neuropathological change found in nearly all individuals with Down's Syndrome over the age of 35 years closely resembles that of Alzheimer's disease. The extent to which dementia occurs as a result of this change is unclear, and the studies which have investigated presumed cognitive deficits are reviewed. The theories put forward to explain the association between these two disorders and their possible significance to the understanding of the aetiology of Alzheimer's disease are discussed.     

Increased superoxide dismutase and Down's syndrome

The enzyme superoxide dismutase (SOD) is a constitutive enzyme coded by a gene located in Chromosome 21 (21q22.1). Thus, the tissues from patients with trisomy 21 contain 50% more SOD activity. It is often suggested that the increased SOD content in the cells of Down's syndrome patients is responsible for many of the neurological symptoms of this disease. This hypothesis is not supported by most of the available data. In this paper we discuss why the increased SOD activity should not influence neuronal function and propose, instead, that the main problem may be an overexpression of other genes also located in chromosome 21 such as the beta amyloid precursor, as well as oncogenes and other Down's syndrome-related genes. We also propose that the increased SOD may be, instead, responsible for the increased incidence of Down's syndrome in children of older women. The augmented antioxidant protection resulting from an extra copy of chromosome 21 may, with time, selectively protect human oocytes from apoptosis, increasing their proportion with age, explaining the higher incidence of this disease.     

A study of digestive absorption in four cases of Down's syndrome. Down's syndrome, malnutrition, malabsorption, and Alzheimer's disease

Many data suggest that patients with Down's syndrome (DS) suffer from digestive malabsorption. A fecal test of absorption (search for undigested meat fibers following the ingestion of a measured diet) was conducted in 4 patients with DS. The results point to malabsorption in these patients and support the hypothesis of malabsorption in DS. The etiology of probable malabsorption in DS is discussed. Data are presented suggesting that chronic malnutrition caused by malabsorption could be the cause of the neuropathologic signs of Alzheimer's disease occurring at or slightly before the fourth decade in all patients with DS.     

Systemic pathology in aged mouse models of Down's syndrome and Alzheimer's disease

Down's syndrome (DS) in humans is caused by trisomy of chromosome 21 (HSA 21). DS patients have a variety of pathologies, including mental retardation and an unusually high incidence of leukemia or lymphoma such as megakaryocytic leukemia. Individuals with DS develop the characteristic neuropathological hallmarks of Alzheimer's disease (AD) in early adulthood, generally by the fourth decade of life. There are several mouse models of DS that have a segmental trisomy of mouse chromosome 16 (MMU 16) with triplicated genes orthologous to HSA 21. These mice display neurodegeneration similar to DS. Although brain pathology in DS models is known, little information is available about other organs. We studied the extraneural pathology in aged DS mice (Ts65Dn, Ts2 and Ts1Cje aged 8 to 24 months) as well as other mouse models of neurodegeneration, including presenilin (PS), amyloid-β precursor protein (APP), and tau (hTau and JNPL) transgenic mice. An increased incidence of peripheral amyloidosis, positive for amyloid A (AA) but not amyloid-β peptide (Aβ), was found in APP over-expressing and tauopathic mice as compared to non-transgenic (ntg) littermates or to DS mouse models. A higher incidence of lymphoma was found in the DS models, including Ts1Cje that is trisomic for a small segment of MMU 16 not including the App gene, but not in the APP over-expressing mice, suggesting that high APP expression is not the cause of lymphoma in DS. The occurrence of lymphomas in mouse DS models is of interest in relation to the increased incidence of malignant conditions in human DS.     

Alzheimer's disease and Down's syndrome: Treating two paths to dementia

Successful therapy of dementia, like any disease, depends upon understanding its pathogenesis. This review contrasts the dominant pathways to dementia which differ in Alzheimer's disease (AD) and in Down's syndrome (DS). Impaired clearance of neurotoxic amyloid beta peptides (Abeta) leads to dementia in AD. In DS over-production of Abeta plays the dominant role in the development of dementia. It follows, therefore, that the therapy of AD and DS should reflect a different balance between the dominant agent that inhibits the synthesis of Abeta in the brain in AD and increase the clearance of Abeta from the cerebrospinal DS.     

Oxidative stress: a bridge between Down's syndrome and Alzheimer's disease

Besides the genetic, biochemical and neuropathological analogies between Down's syndrome (DS) and Alzheimer's disease (AD), there is ample evidence of the involvement of oxidative stress (OS) in the pathogenesis of both disorders. The present paper reviews the publications on DS and AD in the past 10 years in light of the "gene dosage" and "two-hit" hypotheses, with regard to the alterations caused by OS in both the central nervous system and the periphery, and the main pipeline of antioxidant therapeutic strategies. OS occurs decades prior to the signature pathology and manifests as lipid, protein and DNA oxidation, and mitochondrial abnormalities. In clinical settings, the assessment of OS has traditionally been hampered by the use of assays that suffer from inherent problems related to specificity and/or sensitivity, which explains some of the conflicting results presented in this work. For DS, no scientifically proven diet or drug is yet available, and AD trials have not provided a satisfactory approach for the prevention of and therapy against OS, although most of them still need evidence-based confirmation. In the future, a balanced up-regulation of endogenous antioxidants, together with multiple exogenous antioxidant supplementation, may be expected to be one of the most promising treatment methods.     

Amyloid A4 protein and its precursor in Down's syndrome and Alzheimer's disease

In patients with Alzheimer's disease, amyloid fibrils that are aggregates of A4 protein subunits are deposited in the brain. A similar process occurs at an earlier age in persons with Down's syndrome. To investigate the deposition of amyloid in these diseases, we used a radioimmunoassay to measure levels of the amyloid precursor (PreA4) in the serum of 17 patients with Down's syndrome, 15 patients with Alzheimer's disease, and 33 normal elderly controls. The mean (+/- SD) concentration of serum PreA4 was increased 1.5-fold in patients with Down's syndrome (2.49 +/- 1.13 nmol per liter) as compared with that in controls (1.68 +/- 0.49 nmol per liter; P less than 0.007); the levels in patients with Alzheimer's disease were similar to those in controls (1.83 +/- 0.78; P less than 0.98). We also found that the concentration of PreA4 in the brain tissue of two adults with Down's syndrome (100 and 190 pmol per gram) was higher than that in the brain tissue of either 26 patients with Alzheimer's disease (64.4 +/- 17.3 pmol per gram) or 17 elderly controls with neurologic disease (68.5 +/- 26.3 pmol per gram). Immunocytochemical studies of brain tissue from 26 patients with Down's syndrome showed that the deposition of A4 protein amyloid began in these patients approximately 50 years earlier than it began in 127 normal aging subjects studied previously, although the rate of deposition was the same. We conclude that, since the gene for PreA4 is on the long arm of chromosome 21, which is present in triplicate in Down's syndrome, overexpression of this gene may lead to increased levels of PreA4 and amyloid deposition in Down's syndrome. However, since increased levels of PreA4 are not present in Alzheimer's disease, additional factors must account for the amyloid deposition in that disorder.     

Temporal accrual of complement proteins in amyloid plaques in Down's syndrome with Alzheimer's disease

The complement system constitutes a series of enzymatic steps involved in the inflammatory response and is activated in Alzheimer's disease (AD). Using Down's syndrome (DS) brains as a temporal model for the progression of AD, we examined components of the complement cascade and their relationship to other principal events in AD pathology: Abeta42 deposition, neuritic changes, neurofibrillary tangles (NFTs), and gliosis (reactive astrocytes, activated microglia). Adjacent sections of frontal cortex from 24 DS subjects ranging in age from 12 to 73 years were immunohistochemically examined for immunoreactivity (IR) of classical complement proteins (Clq and C3), markers indicating activation of complement (C4d and C5b-9), the complement inhibitor apolipoprotein J (apo J), and markers of AD neuropathology. Abeta42-labeled diffuse plaques were first detected in a 12-year-old DS subject and were not labeled by any of the complement antibodies. Colocalization of Abeta42 with Clq, C3, C4d, and/or apo J was first detected in compacted plaques in the brain of a 15-year-old DS patient with features of mature AD pathology, such as reactive astrocytes, activated microglia, dystrophic neurites, and a few NFTs. IR for C4d and C5b-9 (membrane attack complex, MAC) was observed in small numbers of plaque-associated dystrophic neurites and in focal regions of pyramidal neurons in this 15-year-old. The only other young (相似文献   

Early accumulation of heparan sulfate in neurons and in the beta-amyloid protein-containing lesions of Alzheimer's disease and Down's syndrome.

A monoclonal antibody (HK-249) that recognizes a glucosamine sulfate alpha 1----4 glucuronic acid-containing determinant in heparan sulfate (HS) chains of a basement membrane-derived heparan sulfate proteoglycan identified and immunolocalized HS specifically to the amyloid deposits in neuritic plaques (NPs), congophilic angiopathy (CA), as well as in neurofibrillary tangles (NFTs) and non-tangle-bearing neurons in the brains of Alzheimer's and Down's syndrome (DS) patients. Ultrastructural immunohistochemistry demonstrated that HS within neurons of Alzheimer's disease (AD) brain was localized to lipofuscin granules, an aging pigment previously shown also to contain beta-amyloid protein (BAP). Heparan sulfate also was localized to neurite-containing, nonfibrillar 'primitive' plaques that also demonstrated positive BAP immunoreactivity in both AD and DS brains. Antibodies to laminin, fibronectin, and a chondroitin sulfate proteoglycan failed to show positive immunostaining of the HS-containing sites described above. Analysis of DS patients at different ages revealed that HS accumulated within neurons of the hippocampus and amygdala as early as 1 day after birth. Young age-matched controls did not demonstrate similar positive HS immunoreactivity in neurons, whereas positive immunostaining for HS was observed in other regions thought to normally contain HS. The earliest deposition of BAP was first observed as 'amorphous' or 'diffuse' cortical deposits in DS brain in patients aged 18 and 24 years before the accumulation of fibrillar amyloid (observed in DS patients who are 35 years and older). These cortical deposits also contained positive HS immunoreactivity, implying that HS accumulation in conjunction with the BAP is an early event that ultimately may contribute to the early age-related accumulation (ie, as early as 35 years of age in DS) of NPs, NFTs, and/or CA. Furthermore the colocalization of HS and BAP in a number of specific locales in AD and DS brain indicates a possible interaction between these two macromolecules that may be important in lesion development in these two diseases.     

Regional brain 5-hydroxytryptamine levels are reduced in senile Down's syndrome as in Alzheimer's disease

5-Hydroxytryptamine (5-HT) and choline acetyltransferase (ChAT) were assayed in amygdala, cingulate cortex and caudate nucleus of post-mortem brains from 7 cases of Down's syndrome (6 with the neuropathological features of Alzheimer's disease and one with no such features), 9 cases of Alzheimer's disease and 12 controls. 5-HT was markedly reduced in all 3 areas of the pathologically affected Down brains, unaltered in the Down brain with no Alzheimer pathology and reduced in the amygdala and cingulate cortex of the Alzheimer brains. ChAT showed a similar pattern of reduction. These results supply biochemical evidence that 5-hydroxytryptaminergic, as well as cholinergic, neurons are reduced in Down's syndrome with Alzheimer pathology.     

Cerebral amyloidosis, ageing and Alzheimer's disease; a contribution from studies on Down's syndrome

Observations concerning the time course of deposition of amyloid within the brain substance and blood vessels in persons, of different ages, with Down's syndrome are used to provide a perspective on the nature of the process of cerebral amyloidosis in Alzheimer's disease.     

Differential expression of superoxide dismutases in lung cancer

Oxidant-antioxidant balance is known to regulate growth factors and invasion of tumor cells. Manganese superoxide dismutase (MnSOD), copper zinc SOD (CuZnSOD), and extracellular SOD (ECSOD), the first-line antioxidant defenses, were studied in lung carcinomas by immunohistochemical analysis (n = 139, 56, and 37, respectively) and in 8 lung tumor specimens by Western blot analysis and SOD activity measurement. Altogether, 49% of squamous cell carcinomas and 43% of the adenocarcinomas were positive for MnSOD by immunohistochemical analysis; corresponding values for CuZnSOD were 79% and 93%, respectively. MnSOD and CuZnSOD by Western blot analysis were 27% and 22% higher, and CuZnSOD activity was 93% higher (P = .06) in carcinomas than in nonmalignant lung tissue samples. ECSOD, a mainly extracellular enzyme, showed weak positivity only in 4 of 37 carcinomas, and by Western blot analysis showed 70% lower immunoreactivity (P < .0001) than in nonmalignant lung tissue samples. It is highly likely that low expression of ECSOD might have fundamental effects on the extracellular redox state of lung tumors with potential consequences on tumor behavior.     

Localization of copper-zinc superoxide dismutase mRNA in human hippocampus by in situ hybridization

The cellular localization of copper-zinc superoxide dismutase (CuZn SOD) mRNA was determined in the human hippocampus by in situ hybridization with a 35S-labelled DNA probe complementary to human CuZn SOD mRNA. A positive hybridization signal was detected in pyramidal cell layers CA1-CA4 of Ammon's horn (CA), pyramidal cells of subiculum and in the granule cells of the dentate gyrus. The fact that CuZn SOD gene expression is important in neurones which are preferentially vulnerable in neurodegenerative processes such as Alzheimer's disease, suggests a role played by oxygen free radicals in the mechanism of nerve cell death.     

Gene polymorphisms of superoxide dismutases and catalase in diabetes mellitus

Background  

Reactive oxygen species generated by hyperglycaemia modify structure and function of lipids, proteins and other molecules taking part in chronic vascular changes in diabetes mellitus (DM). Low activity of scavenger enzymes has been observed in patients with DM. Protective role of scavenger enzymes may be deteriorated by oxidative stress. This study was undertaken to investigate the association between gene polymorphisms of selected antioxidant enzymes and vascular complications of DM.     

Increase of immunoglobulin G3 subclass is related to brain autoantibody in Alzheimer's disease but not in Down's syndrome

The proportions of IgG subclasses (G1, G2, G3 and G4) were quantified in sera from Alzheimer's disease (AD) patients, older Down's syndrome (DS) patients and age-matched controls. The levels of IgG1, IgG2 and IgG4 were normal in AD patients, but the proportions of IgG3 were significantly elevated in 9 of 20 (45%) patients (0.803 +/- 0.141 mg/ml; p less than 0.001) compared to the level found in age-matched controls (0.471 +/- 0.161 mg/ml; n = 10). The IgG3 level in the remaining 11 AD patients was slightly lower than the controls (0.385 +/- 0.104 vs. 0.471 +/- 0.161 mg/ml), but it did not reach statistical significance (p = 0.149). In contrast, patients with DS displayed imbalance of IgG2, IgG3, and IgG4 subclasses; they had significantly increased IgG3 but decreased IgG2 and IgG4 levels. The IgG1 level was within normal range. Moreover, a majority of AD sera (8 of 9) with elevated IgG3 concentration were positive for brain autoantibody. The remaining 11 AD sera without elevated IgG3 level, all DS sera and all control sera were negative for brain autoantibody. This finding indirectly suggests that brain autoantibody is mainly due to IgG3 subclass, at least in one subset of AD patients.     

Constant neurofibrillary changes in the neocortex in progressive supranuclear palsy. Basic differences with Alzheimer's disease and aging.

Neocortical neurofibrillary tangles (NFT) revealed by Bodian technique and anti-tau immunolabelling were seen in 5/5 cases of progressive supranuclear palsy (PSP) aged 58-76 years. These lesions differed from Alzheimer's disease or age-related changes: (1) they were most frequent in the precentral gyrus (Brodmann's area 4) whereas associative areas are predominantly lesioned in Alzheimer's disease; (2) they affected mainly large pyramidal neurons and small cells, relatively sparing the cell population selectively involved in Alzheimer's disease; (3) they predominated in layers V and VI of area 4, whereas NFT are most dense in layers III and V in Alzheimer's disease; (4) mature senile plaques (1/5 cases) and beta-amyloid diffuse deposits (3/5 cases), which usually precede or go together with NFT in Alzheimer's disease were rare or absent (2/5) in PSP. Neuropil threads and tufts of abnormal fibres were also seen. In addition, NFT and neuropil threads were found in the hippocampus. PSP is thus another example of abnormal storage of tau developing in the neocortex in the absence of beta-amyloid deposits. It might prove a useful model for the understanding of the mechanisms of localization and spreading of tau storage in the brain.