Profiling proteins related to amyloid deposited brain of Tg2576 mice

Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by the extracellular deposition of beta-amyloid and intracellular hyperphosphorylation of tau in the cortex and hippocampus of the brain. These characterizations are caused by abnormal expression, modification and deposition of certain proteins. Post-translational modifications of proteins including oxidation and nitration might be involved in the pathogenesis of AD. In this study, AD-related proteins were identified in the cortex of Tg2576 mice used as a model for studying AD. Tg2576 mice express high levels of the Swedish mutated form of human beta-amyloid precursor protein (APP) and generated high levels of beta-amyloid in the brains. Using Western blotting and two-dimensional electrophoresis, proteins with differences in expression, oxidation and nitration in the cortex of Tg2576 mice brains were compared to littermate mice brains used as a control. The proteins with different expression levels were identified using matrix-assisted laser desorption/ionization-time of flight and liquid chromatography-tandem mass spectrometry analyses. As a result, 12 proteins were identified among 37 different proteins using the PDQuest program. Furthermore, two proteins, laminin receptor and alpha-enolase, were more susceptible to oxidative modification in the brains of Tg2576 mice compared to those of littermates. Similarly, alpha-enolase, calpain 12, and Atp5b were more modified by nitration in brains of Tg2576 mice than those of littermates. Taken together, these proteins and their modifications may play an important role in the plaque deposition of Tg2576 mice brains.     

Differential brain expression of the Alzheimer''s amyloid precursor protein.

The expression of the Alzheimer amyloid protein precursor (AAPP) was examined in human, monkey, dog and rat brains. Two proteins, one identified as AAPP695 and the other as AAPP751, were immunoprecipitated from the in vitro translation of human, dog and rat brain polysomes. The AAPP751 to AAPP695 ratio was highest in human, intermediate in dog and lowest in rat brain polysomes. Human cerebral cortex contained higher levels of the AAPP751 mRNA than either dog or rat cortex. AAPP695 was detected in both cerebral cortex and cerebellum of all species examined. In contrast, AAPP751 was detected predominantly in the cortex of human, monkey and to a lesser extent dog brains while it was not detected in rat brain. These findings indicate that the amyloid precursors are differentially expressed in different mammalian brains and suggest that AAPP751 is mainly expressed in the brain regions involved in plaque formation.     

Topographic determination of zinc in human brain by atomic absorption spectrophotometry

Atomic absorption spectroscopy was used for measuring the zinc content, in ppb (μg/1), of brain tissue. A new method for determining the correction factor of atomic absorption interference is described. Measurements of the zinc content of twenty-four regions of adult human brains showed the maximum zinc content in resistent sector and endplate of the Amnion's horn, corroborating the histochemical data. The distribution of zinc in other regions was relatively uniform, but white matter showed lower values than gray matter. The zinc content of seventeen regions of human newborn brains was below that in adult brains, for all regions. The blood content of brain tissue contributed only insignificantly to its zinc content.     

Neurocupein from human brain

The copper-containing protein, neurocuprein, has been obtained in a highly purified state from human brain. Many similarities in properties of neurocupreins from human and bovine brains are noted. These concern molecular weights, copper contents, isoelectric points, amino acid compositions, optical and EPR spectra as well as their reaction with catecholamines. However, it was found that the content of neurocuprein in the whole human brain is significantly (by a factor 2.5–3.0) higher than in bovine brain.     

Survival of the fattest: fat babies were the key to evolution of the large human brain

In the past 2 million years, the hominid lineage leading to modern humans evolved significantly larger and more sophisticated brains than other primates. We propose that the modern human brain was a product of having first evolved fat babies. Hence, the fattest (infants) became, mentally, the fittest adults. Human babies have brains and body fat each contributing to 11-14% of body weight, a situation which appears to be unique amongst terrestrial animals. Body fat in human babies provides three forms of insurance for brain development that are not available to other land-based species: (1) a large fuel store in the form of fatty acids in triglycerides; (2) the fatty acid precursors to ketone bodies which are key substrates for brain lipid synthesis; and (3) a store of long chain polyunsaturated fatty acids, particularly docosahexaenoic acid, needed for normal brain development. The triple combination of high fuel demands, inability to import cholesterol or saturated fatty acids, and dependence on docosahexaenoic acid puts the mammalian brain in a uniquely difficult situation compared with other organs and makes its expansion in early humans all the more remarkable. We believe that fresh- and salt-water shorelines provided a uniquely rich, abundant and accessible food supply, and the only viable environment for evolving both body fat and larger brains in human infants.     

Isolation and characterization of two isomers of brain tetrasialogangliosides.

Two isomers of tetrasialogangliosides were isolated and purified to homogeneity from human, bovine, chicken, and cod fish brains by employing DEAE-Sephadex and Iatrobeads column chromatographies. The tetrasialogangliosides of human, bovine, and chicken brains appeared to be identical because they had identical mobilities on thin layer plates developed with six different solvent systems. The tetrasialoganglioside of cod fish brain moved slower on thin layer plates than the tetrasialoganglioside from the other species. The ganglioside preparations were subjected to mild acid hydrolysis, neuraminidase treatment, and periodate oxidation followed by borohydride reduction. The structures of the two isomers were differentiated from each other by controlled mild acid hydrolysis in both aqueous and organic solvents. The structure IV3(NeuAc)2,II3(NeuAc)2-GgOse4ceramide is assigned to the tetrasialoganglioside of human, bovine, and chicken brains; and the structure IV3NeuAc,II2(NeuAc)3-GgOse4ceramide is assigned to that of cod fish brain. The possible pathways for the synthesis of the two tetrasialogangliosides are discussed.     

The mitochondrial brain: From mitochondrial genome to neurodegeneration

Mitochondrial DNA mutations are an important cause of neurological disease. The clinical presentation is very varied in terms of age of onset and different neurological signs and symptoms. The clinical course varies considerably but in many patients there is a progressive decline, and in some evidence of marked neurodegeneration. Our understanding of the mechanisms involved is limited due in part to limited availability of animal models of disease. However, studies on human post-mortem brains, combined with clinical and radiological studies, are giving important insights into specific neuronal involvement.     

Calmodulin in brain of schizophrenics

A heat-stable Ca²⁺-dependent regulator protein with the characteristics of calmodulin was extracted and purified from striatum and cerebral cortex of autopsied human brains. The human calmodulin preparation cross-reacts with Ca²⁺-dependent phosphodiesterase isolated from rat, bovine, and human cerebral cortex. There was no significant difference between calmodulin content measured in membranes obtained from striatum or cortex of nine control subjects without a psychiatric history and seven schizophrenic individuals.     

Human brain GABA transaminase is immunologically distinct from those of other mammalian brains

Monoclonal antibodies (mAbs) to bovine brain γ-aminobutyric acid (GABA) transaminase were characterized by epitope mapping analysis, and used as probes to compare the epitopes of the enzymes from several mammalian brains including man. From the epitope mapping analysis, three subgroups of mAbs recognizing different peptide fragments were identified. In the immunoblots probed with the mAbs, only one out of the three subgroups of mAbs reacted with a protein band of 50 kDa from human brain; the two other mAbs failed to detect any signal on the blots. In contrast, all of the mAbs did recognize a GABA-T protein band on immunoblots of all other mammalian brains tested. The results suggest that human brain GABA transaminase is immunologically distinct from those of other mammalian brains.     

The relevance of brain evolution for the biomedical sciences

Most biomedical neuroscientists realize the importance of the study of brain evolution to help them understand the differences and similarities between their animal model of choice and the human brains in which they are ultimately interested. Many think of evolution as a linear process, going from simpler brains, as those of rats, to more complex ones, as those of humans. However, in reality, every extant species' brain has undergone as long a period of evolution as has the human brain, and each brain has its own species-specific adaptations. By understanding the variety of existing brain types, we can more accurately reconstruct the brains of common ancestors, and understand which brain traits (of humans as well as other species) are derived and which are ancestral. This understanding also allows us to identify convergently evolved traits, which are crucial in formulating hypotheses about structure-function relationships in the brain. A thorough understanding of the processes and patterns of brain evolution is essential to generalizing findings from 'model species' to humans, which is the backbone of modern biomedical science.     

Connexin expression in Huntington's diseased human brain

In Huntington's diseased human brain, it is in the caudate nucleus (CN) and globus pallidus (GP) of the basal ganglia where nerve cell death is seen most dramatically. The distribution of five gap junction proteins (connexins 26, 32, 40, 43 and 50) has been examined in these areas in normal and Huntington's diseased human brain using immunohistochemical techniques. There was no Cx50 expression observed and Cx40 was localized in the endothelial cells of blood vessels, with the Huntington's diseased brains having more numerous and smaller blood vessels than normal tissue. Cx26 and Cx32 revealed a similar distribution pattern to each other in both normal and diseased brains with little labelling in the CN but clear labelling in the GP. Cx43, expressed by astrocytes, was the most abundant connexin type of those studied. In both normal and diseased brains Cx43 in the GP was homogeneously distributed in the neuropil. In the CN, however, Cx43 density was both increased with Huntington's disease and became located in patches. Glial fibrillary acidic protein(GFAP) staining of astrocytes was also highly increased in the CN compared with normal brains. These labelling patterns indicate a reactive astrocytosis around degenerating neurons with an increased expression of astrocytic gap junctions. The enhanced coupling state between astrocytes, assuming the junctions are functional, could provide an increased spatial buffering capacity by the astrocytes in an attempt to maintain a proper environment for the neurons, helping promote neuronal survival in this neurodegenerative disorder.     

Innovation in the collective brain

Innovation is often assumed to be the work of a talented few, whose products are passed on to the masses. Here, we argue that innovations are instead an emergent property of our species'' cultural learning abilities, applied within our societies and social networks. Our societies and social networks act as collective brains. We outline how many human brains, which evolved primarily for the acquisition of culture, together beget a collective brain. Within these collective brains, the three main sources of innovation are serendipity, recombination and incremental improvement. We argue that rates of innovation are heavily influenced by (i) sociality, (ii) transmission fidelity, and (iii) cultural variance. We discuss some of the forces that affect these factors. These factors can also shape each other. For example, we provide preliminary evidence that transmission efficiency is affected by sociality—languages with more speakers are more efficient. We argue that collective brains can make each of their constituent cultural brains more innovative. This perspective sheds light on traits, such as IQ, that have been implicated in innovation. A collective brain perspective can help us understand otherwise puzzling findings in the IQ literature, including group differences, heritability differences and the dramatic increase in IQ test scores over time.     

Biochemical characterization of alpha-adrenergic receptors in human brain and changes in Alzheimer-type dementia

Using ligand binding techniques, we studied alpha-adrenergic receptors in brains obtained at autopsy from seven histologically normal controls and seven patients with histopathologically verified Alzheimer-type dementia (ATD). Binding of the alpha-adrenergic antagonists [3H]prazosin and [3H]yohimbine to membranes of human brains exhibited characteristics compatible with alpha 1- and alpha 2-adrenergic receptors, respectively. Binding of both ligands was saturable and reversible, with dissociation constants of 0.15 nM for [3H]prazosin and 5.5 nM for [3H]yohimbine. [3H]Prazosin binding was highest in the hippocampus and frontal cortex and lowest in the caudate and putamen in the control brains. [3H]Yohimbine binding was highest in the nucleus basalis of Meynert (NbM) and frontal cortex and lowest in the caudate and cerebellar hemisphere in the control brains. Compared with values for the controls, [3H]prazosin binding sites were significantly reduced in number in the hippocampus and cerebellar hemisphere, and [3H]yohimbine binding sites were significantly reduced in number in the NbM in the ATD brains. These results suggest that alpha 1- and alpha 2-adrenergic receptors are present in the human brain and that there are significant changes in numbers of both receptors in selected regions in patients with ATD.     

Radioimmunoassay for brain natriuretic peptide (BNP) detection of BNP in canine brain

We established a highly sensitive and specific radioimmunoassay (RIA) for BNP. Our RIA detected BNP-like immunoreactivity (-LI) in the porcine and canine brains but did not detect BNP-LI in the human, monkey or rat brain. The widespread distribution of BNP-LI was demonstrated both in the porcine and canine brains, with the highest concentration in the medulla oblongata. In contrast, the highest concentration of ANP-LI determined simultaneously was in the midbrain and the olfactory bulb. High performance-gel permeation chromatography coupled with RIA revealed that the major component of BNP-LI was eluted at the position of synthetic BNP with a small molecular weight (3K). These results indicate that the RIA for BNP serves as a useful tool to investigate physiological roles of BNP.     

Demonstration of brain capillaries using acetyl-CoA]

The method is based on a reduced procedure for revealing cholinacetyltransferase when the stage of preincubation treatment of the material and inhibitor is omitted. The possibility to investigate the human and animal brains with a complete revealing of the capillary network, which corresponds to injection of the vessels with Indian ink, is proved.     

PINK1 kinase dysfunction triggers neurodegeneration in the primate brain without impacting mitochondrial homeostasis

In vitro studies have established the prevalent theory that the mitochondrial kinase PINK1 protects neurodegeneration by removing damaged mitochondria in Parkinson's disease(PD).However,difficulty in detecting endogenous PINK1 protein in rodent brains and cell lines has prevented the rigorous investigation of the in vivo role of PINK1.Here we report that PINK1 kinase form is selectively expressed in the human and monkey brains.CRISPR/Cas9-mediated deficiency of PINK1 causes similar neurodegeneration in the brains of fetal and adult monkeys as well as cultured monkey neurons without affecting mitochondrial protein expression and morphology.Importantly,PINK1 mutations in the primate brain and human cells reduce protein phosphorylation that is important for neuronal function and survival.Our findings suggest that PINK1 kinase activity rather than its mitochondrial function is essential for the neuronal survival in the primate brains and that its kinase dysfunction could be involved in the pathogenesis of PD.     

Possible metabolic constraints on human brain weight at birth

Having humans born with adult-size brains would entail only a small and readily evolved increase in the size of the human female birth canal. The explanation for the present size of the human brain at birth is then plausibly based on the upper limit of brain that can be nourished by present human nutritional strategies. This limit turns out to be about 10% of the body weight of the newborn infant, in agreement with the actual value.     

Metabolism of ethanol by human brain to fatty acid ethyl esters

Although the most prominent acute and chronic effect of alcohol ingestion in man is alteration of brain function, metabolism of ethanol by human brain has not been documented. This study was designed to detect and localize a new family of nonoxidative ethanol metabolites, fatty acid ethyl esters, in human brain and characterize their synthetic pathways. Fatty acid ethyl ester synthase activity was present in 10 different locations in human brain, with gray matter containing more activity than white matter (0.53 nmol of ethyl oleate/mg of protein/h and 0.25 nmol of ethyl oleate/mg of protein/h, respectively). Two forms of this synthase, present in cytosol or loosely bound to membrane fractions, were isolated from human gray and white matter and then partially purified by ion-exchange chromatography. Both were active at low ethanol concentrations easily attained in vivo in man. Importantly, fatty acid ethyl esters were also detected in brains of individuals dying while intoxicated; only small amounts were present in control subjects at autopsy. Thus, alcohol metabolism in human brain has been documented for the first time by identifying both fatty acid ethyl esters and their synthases in this important target-organ of alcohol abuse.     

内源性神经干细胞与脑老化的治疗

近十几年研究发现成年人脑神经元可以再生,使人们重新认识老年脑神经细胞的可塑性,它为脑损伤的修复带来新的希望。最新研究表明,神经再生可被调控,是一种新的修复机制。这使得利用内源性神经干细胞治疗老龄相关的神经退行性疾病成为可能。