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1.
The amyloid beta protein is deposited in the brains of patients with Alzheimer's disease but its pathogenic role is unknown. In culture, the amyloid beta protein was neurotrophic to undifferentiated hippocampal neurons at low concentrations and neurotoxic to mature neurons at higher concentrations. In differentiated neurons, amyloid beta protein caused dendritic and axonal retraction followed by neuronal death. A portion of the amyloid beta protein (amino acids 25 to 35) mediated both the trophic and toxic effects and was homologous to the tachykinin neuropeptide family. The effects of the amyloid beta protein were mimicked by tachykinin antagonists and completely reversed by specific tachykinin agonists. Thus, the amyloid beta protein could function as a neurotrophic factor for differentiating neurons, but at high concentrations in mature neurons, as in Alzheimer's disease, could cause neuronal degeneration.  相似文献   

2.
The secondary structures in solution of the synthetic, naturally occurring, amyloid beta peptides, residues 1 to 42 [beta (1-42)] and beta (1-39), and related fragments, beta (1-28) and beta (29-42), have been studied by circular dichroism and two-dimensional nuclear magnetic resonance spectroscopy. In patients with Alzheimer's disease, extracellular amyloid plaque core is primarily composed of beta (1-42), whereas cerebrovascular amyloid contains the more soluble beta (1-39). In aqueous trifluoroethanol solution, the beta (1-28), beta (1-39), and beta (1-42) peptides adopt monomeric alpha-helical structures at both low and high pH, whereas at intermediate pH (4 to 7) an oligomeric beta structure (the probable structure in plaques) predominates. Thus, beta peptide is not by itself an insoluble protein (as originally thought), and localized or normal age-related alterations of pH may be necessary for the self-assembly and deposition of beta peptide. The hydrophobic carboxyl-terminal segment, beta(29-42), exists exclusively as an oligomeric beta sheet in solution, regardless of differences in solvent, pH, or temperature, suggesting that this segment directs the folding of the complete beta (1-42) peptide to produce the beta-pleated sheet found in amyloid plaques.  相似文献   

3.
Amyloid fibrils commonly exhibit multiple distinct morphologies in electron microscope and atomic force microscope images, often within a single image field. By using electron microscopy and solid-state nuclear magnetic resonance measurements on fibrils formed by the 40-residue beta-amyloid peptide of Alzheimer's disease (Abeta(1-40)), we show that different fibril morphologies have different underlying molecular structures, that the predominant structure can be controlled by subtle variations in fibril growth conditions, and that both morphology and molecular structure are self-propagating when fibrils grow from preformed seeds. Different Abeta(1-40) fibril morphologies also have significantly different toxicities in neuronal cell cultures. These results have implications for the mechanism of amyloid formation, the phenomenon of strains in prion diseases, the role of amyloid fibrils in amyloid diseases, and the development of amyloid-based nano-materials.  相似文献   

4.
The amyloid beta peptide (A beta P) is a small fragment of the much larger, broadly distributed amyloid precursor protein (APP). Abundant A beta P deposition in the brains of patients with Alzheimer's disease suggests that altered APP processing may represent a key pathogenic event. Direct protein structural analyses showed that constitutive processing in human embryonic kidney 293 cells cleaves APP in the interior of the A beta P, thus preventing A beta P deposition. A deficiency of this processing event may ultimately prove to be the etiological event in Alzheimer's disease that gives rise to senile plaque formation.  相似文献   

5.
We identified axonal defects in mouse models of Alzheimer's disease that preceded known disease-related pathology by more than a year; we observed similar axonal defects in the early stages of Alzheimer's disease in humans. Axonal defects consisted of swellings that accumulated abnormal amounts of microtubule-associated and molecular motor proteins, organelles, and vesicles. Impairing axonal transport by reducing the dosage of a kinesin molecular motor protein enhanced the frequency of axonal defects and increased amyloid-beta peptide levels and amyloid deposition. Reductions in microtubule-dependent transport may stimulate proteolytic processing of beta-amyloid precursor protein, resulting in the development of senile plaques and Alzheimer's disease.  相似文献   

6.
The formation of clusters of altered axons and dendrites surrounding extracellular deposits of amyloid filaments (neuritic plaques) is a major feature of the human brain in both aging and Alzheimer's disease. A panel of antibodies against amyloid filaments and their constituent proteins from humans with Alzheimer's disease cross-reacted with neuritic plaque and cerebrovascular amyloid deposits in five other species of aged mammals, including monkey, orangutan, polar bear, and dog. Antibodies to a 28-amino acid peptide representing the partial protein sequence of the human amyloid filaments recognized the cortical and microvascular amyloid of all of the aged mammals examined. Plaque amyloid, plaque neurites, and neuronal cell bodies in the aged animals showed no reaction with antibodies to human paired helical filaments. Thus, with age, the amyloid proteins associated with progressive cortical degeneration in Alzheimer's disease are also deposited in the brains of other mammals. Aged primates can provide biochemically relevant models for principal features of Alzheimer's disease: cerebrovascular amyloidosis and neuritic plaque formation.  相似文献   

7.
Alzheimer's disease is characterized by widespread deposition of amyloid in the central nervous system. The 4-kilodalton amyloid beta protein is derived from a larger amyloid precursor protein and forms amyloid deposits in the brain by an unknown pathological mechanism. Except for aged nonhuman primates, there is no animal model for Alzheimer's disease. Transgenic mice expressing amyloid beta protein in the brain could provide such a model. To investigate this possibility, the 4-kilodalton human amyloid beta protein was expressed under the control of the promoter of the human amyloid precursor protein in two lines of transgenic mice. Amyloid beta protein accumulated in the dendrites of some but not all hippocampal neurons in 1-year-old transgenic mice. Aggregates of the amyloid beta protein formed amyloid-like fibrils that are similar in appearance to those in the brains of patients with Alzheimer's disease.  相似文献   

8.
The distribution of cells containing messenger RNA that encodes amyloid beta protein was determined in hippocampi and in various cortical regions from cynomolgus monkeys, normal humans, and patients with Alzheimer's disease by in situ hybridization. Both 35S-labeled RNA antisense and sense probes to amyloid beta protein messenger RNA were used to ensure specific hybridization. Messenger RNA for amyloid beta protein was expressed in a subset of neurons in the prefrontal cortex from monkeys, normal humans, and patients with Alzheimer's disease. This messenger RNA was also present in the neurons of all the hippocampal fields from monkeys, normal humans and, although to a lesser extent in cornu ammonis 1, patients with Alzheimer's disease. The distribution of amyloid beta protein messenger RNA was similar to that of the neurofibrillary tangles of Alzheimer's disease in some regions, but the messenger RNA was also expressed in other neurons that are not usually involved in the pathology of Alzheimer's disease.  相似文献   

9.
The amyloid beta protein peptide is a major constituent of amyloid plaque cores in Alzheimer's disease and is apparently derived from a higher molecular weight precursor. It is now shown that the core protein of a heparan sulfate proteoglycan secreted from a nerve cell line (PC12) has an amino acid sequence and a size very similar to those of the amyloid beta protein precursor and that these molecules are antigenically related. This amyloid beta protein precursor-related protein is not found in the conditioned medium of a variant cell line (F3 PC12) that does not secrete heparan sulfate proteoglycan. The synaptic localization and metabolism of this class of proteoglycans are consistent with its potential involvement in central nervous system dysfunction.  相似文献   

10.
With the recently cloned complementary DNA probe, lambda Am4 for the chromosome 21 gene encoding brain amyloid polypeptide (beta amyloid protein) of Alzheimer's disease, leukocyte DNA from three patients with sporadic Alzheimer's disease and two patients with karyotypically normal Down syndrome was found to contain three copies of this gene. Because a small region of chromosome 21 containing the ets-2 gene is duplicated in patients with Alzheimer's disease, as well as in karyotypically normal Down syndrome, duplication of a subsection of the critical segment of chromosome 21 that is duplicated in Down syndrome may be the genetic defect in Alzheimer's disease.  相似文献   

11.
Human hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D), an autosomal dominant form of cerebral amyloid angiopathy (CAA), is characterized by extensive amyloid deposition in the small leptomeningeal arteries and cortical arterioles, which lead to an early death of those afflicted in their fifth or sixth decade. Immunohistochemical and biochemical studies have indicated that the amyloid subunit in HCHWA-D is antigenically related to and homologous in sequence with the amyloid beta protein isolated from brains of patients with Alzheimer's disease and Down syndrome. The amyloid beta protein is encoded by the amyloid beta protein precursor (APP) gene located on chromosome 21. Restriction fragment length polymorphisms detected by the APP gene were used to examine whether this gene is a candidate for the genetic defect in HCHWA-D. The data indicate that the APP gene is tightly linked to HCHWA-D and therefore, in contrast to familial Alzheimer's disease, cannot be excluded as the site of mutation in HCHWA-D.  相似文献   

12.
Alzheimer's disease is a synaptic failure   总被引：1，自引：0，他引：1  
In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein.  相似文献   

13.
Amyloid deposition in senile plaques and the cerebral vasculature is a marker of Alzheimer's disease. Whether amyloid itself contributes to the neurodegenerative process or is simply a by-product of that process is unknown. Pheochromocytoma (PC12) and fibroblast (NIH 3T3) cell lines were transfected with portions of the gene for the human amyloid precursor protein. Stable PC12 cell transfectants expressing a specific amyloid-containing fragment of the precursor protein gradually degenerated when induced to differentiate into neuronal cells with nerve growth factor. Conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against the amyloid polypeptide. Thus, a peptide derived from the amyloid precursor may be neurotoxic.  相似文献   

14.
Complementary DNAs (cDNAs) encoding portions of the amyloid beta protein were used to investigate possible amyloid gene duplication in sporadic Alzheimer's disease. A strategy employing two Eco RI restriction fragment length polymorphisms (RFLPs) detected by the amyloid cDNAs was used. RFLPs allow the detection of a 2:1 gene dosage in the DNA of any individual who is heterozygous for a particular RFLP. The amyloid gene regions homologous to the cDNAs used were not duplicated in the DNA from brains of individuals with sporadic Alzheimer's disease. Similar results were also obtained with a strategy employing a test for 3:2 gene dosage.  相似文献   

15.
Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Here, we demonstrate that Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients and transgenic mice. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. Transgenic mice overexpressing ABAD in an Abeta-rich environment manifest exaggerated neuronal oxidative stress and impaired memory. These data suggest that the ABAD-Abeta interaction may be a therapeutic target in AD.  相似文献   

16.
Alzheimer's disease is a form of localized amyloidosis characterized by cerebral cortical amyloid plaques, neurofibrillary tangles, and amyloid deposits within the walls of leptomeningeal vessels. Although most cases of Alzheimer's disease are sporadic, kindreds with autosomal-dominant inheritance of the syndrome suggest that a single mutation may be important in pathogenesis. Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein. This mutation correlates with the presence of Alzheimer's disease in all patients in this study, and may be the inherited factor causing both amyloid fibril formation and dementia.  相似文献   

17.
Many potential treatments for Alzheimer's disease target amyloid-beta peptides (Abeta), which are widely presumed to cause the disease. The microtubule-associated protein tau is also involved in the disease, but it is unclear whether treatments aimed at tau could block Abeta-induced cognitive impairments. Here, we found that reducing endogenous tau levels prevented behavioral deficits in transgenic mice expressing human amyloid precursor protein, without altering their high Abeta levels. Tau reduction also protected both transgenic and nontransgenic mice against excitotoxicity. Thus, tau reduction can block Abeta- and excitotoxin-induced neuronal dysfunction and may represent an effective strategy for treating Alzheimer's disease and related conditions.  相似文献   

18.
The incidence of Alzheimer's disease (AD) and that of prion disorders (PrD) could not be more different. One-third of octogenarians succumb to AD, whereas Creutzfeldt-Jakob disease typically affects one individual in a million each year. However, these diseases have many common features impinging on the metabolism of neuronal membrane proteins: the amyloid precursor protein APP in the case of AD, and the cellular prion protein PrPC in PrD. APP begets the Abeta peptide, whereas PrPC begets the malignant prion protein PrPSc. Both Abeta and PrPSc are associated with disease, but we do not know what triggers their accumulation and neurotoxicity. A great deal has been learned, however, about protein folding, misfolding, and aggregation; an entirely new class of intramembrane proteases has been identified; and unsuspected roles for the immune system have been uncovered. There is reason to expect that prion research will profit from advances in the understanding of AD, and vice versa.  相似文献   

19.
A subset of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to preferentially reduce the secretion of the highly amyloidogenic, 42-residue amyloid-beta peptide Abeta42. We found that Rho and its effector, Rho-associated kinase, preferentially regulated the amount of Abeta42 produced in vitro and that only those NSAIDs effective as Rho inhibitors lowered Abeta42. Administration of Y-27632, a selective Rock inhibitor, also preferentially lowered brain levels of Abeta42 in a transgenic mouse model of Alzheimer's disease. Thus, the Rho-Rock pathway may regulate amyloid precursor protein processing, and a subset of NSAIDs can reduce Abeta42 through inhibition of Rho activity.  相似文献   

20.
Four clones were isolated from an adult human brain complementary DNA library with an oligonucleotide probe corresponding to the first 20 amino acids of the beta peptide of brain amyloid from Alzheimer's disease. The open reading frame of the sequenced clone coded for 97 amino acids, including the known amino acid sequence of this polypeptide. The 3.5-kilobase messenger RNA was detected in mammalian brains and human thymus. The gene is highly conserved in evolution and has been mapped to human chromosome 21.  相似文献   

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