Interaction between Aβ Peptide and α Synuclein: Molecular Mechanisms in Overlapping Pathology of Alzheimer’s and Parkinson’s in Dementia with Lewy Body Disease

Amyloidogenic proteins (Aβ peptide) in Alzheimer’s disease (AD) and alpha-synuclein (α-Syn) in Parkinson’s disease (PD) are typically soluble monomeric precursors, which undergo remarkable conformational changes and culminate in the form of aggregates in diseased condition. Overlap of clinical and neuropathological features of both AD and PD are observed in dementia with Lewy body (DLB) disease, the second most common form of dementia after AD. The identification of a 35-amino acid fragment of α-Syn in the amyloid plaques in DLB brain have raised the possibility that Aβ and α-Syn interact with each other. In this report, the molecular interaction of α-Syn with Aβ40 and/or Aβ42 are investigated using multidimensional NMR spectroscopy. NMR data in the membrane mimic environment indicate specific sites of interaction between membrane-bound α-Syn with Aβ peptide and vice versa. These Aβ–α-Syn interactions are demonstrated by reduced amide peak intensity or change in chemical shift of amide proton of the interacting proteins. Based on NMR results, the plausible molecular mechanism of overlapping pathocascade of AD and PD in DLB due to interactions between α-Syn and Aβ is described. To the best of our knowledge, it is the first report using multidimensional NMR spectroscopy that elucidates molecular interactions between Aβ and α-Syn which may lead to onset of DLB. An erratum to this article can be found at     

Delineating the Mechanism of Alzheimer’s Disease Aβ Peptide Neurotoxicity

The Alzheimer’s disease neurotoxic amyloid-β (Aβ) peptide is derived from the larger amyloid precursor protein (APP) and is the principal component of the senile plaques in Alzheimer’s disease (AD) brains. This mechanism by which Aβ mediates neurotoxicity or neuronal dysfunction is not fully resolved. This review will outline some of the key determinants that modulate Aβ’s activity and the cellular pathways and mechanisms involved.     

Free Copper,Ferroxidase and SOD1 Activities,Lipid Peroxidation and NO<Subscript><Emphasis Type="Italic">x</Emphasis></Subscript> Content in the CSF. A Different Marker Profile in Four Neurodegenerative Diseases

The understanding of oxidative damage in different neurodegenerative diseases could enhance therapeutic strategies. Our objective was to quantify lipoperoxidation and other oxidative products as well as the activity of antioxidant enzymes and cofactors in cerebrospinal fluid (CSF) samples. We recorded data from all new patients with a diagnosis of either one of the four most frequent neurodegenerative diseases: Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD) and lateral amyotrophic sclerosis (ALS). The sum of nitrites and nitrates as end products of nitric oxide (NO) were increased in the four degenerative diseases and fluorescent lipoperoxidation products in three (excepting ALS). A decreased Cu/Zn-dependent superoxide dismutase (SOD) activity characterized the four diseases. A significantly decreased ferroxidase activity was found in PD, HD and AD, agreeing with findings of iron deposition in these entities, while free copper was found to be increased in CSF and appeared to be a good biomarker of PD.     

Isofurans,but not F2-isoprostanes,are increased in the substantia nigra of patients with Parkinson's disease and with dementia with Lewy body disease

F2-isoprostanes (F2-IsoPs) are well-established sensitive and specific markers of oxidative stress in vivo. Isofurans (IsoFs) are also products of lipid peroxidation, but in contrast to F2-IsoPs, their formation is favored when oxygen tension is increased in vitro or in vivo. Mitochondrial dysfunction in Parkinson's disease (PD) may not only lead to oxidative damage to brain tissue but also potentially result in increased intracellular oxygen tension, thereby influencing relative concentrations of F2-IsoPs and IsoFs. In this study, we attempted to compare the levels of F2-IsoPs and IsoFs esterified in phospholipids in the substantia nigra (SN) from patients with PD to those of age-matched controls as well as patients with other neurodegenerative diseases, including dementia with Lewy body disease (DLB), multiple system atrophy (MSA), and Alzheimer's disease (AD). The results demonstrated that IsoFs but not F2-IsoPs in the SN of patients with PD and DLB were significantly higher than those of controls. Levels of IsoFs and F2-IsoPs in the SN of patients with MSA and AD were indistinguishable from those of age-matched controls. This preferential increase in IsoFs in the SN of patients with PD or DLB not only indicates a unique mode of oxidant injury in these two diseases but also suggests different underlying mechanisms of dopaminergic neurodegeneration in PD and DLB from those of MSA.     

Humanin and the Receptors for Humanin

Alzheimer’s disease (AD) is a prevalent dementia-causing neurodegenerative disease. Neuronal death is closely linked to the progression of AD-associated dementia. Accumulating evidence has established that a 24-amino-acid bioactive peptide, Humanin, protects neurons from AD-related neuronal death. A series of studies using various murine AD models including familial AD gene-expressing transgenic mice have shown that Humanin is effective against AD-related neuronal dysfunction in vivo. Most recently, it has been shown that Humanin inhibits neuronal cell death and dysfunction by binding to a novel IL-6-receptor-related receptor(s) on the cell surface involving CNTFRα, WSX-1, and gp130. These findings suggest that endogenous Humanin [or a Humanin-like substance(s)] may suppress the onset of AD-related dementia by inhibiting both AD-related neuronal cell death and dysfunction.     

Natural Antioxidants Protect Neurons in Alzheimer’s Disease and Parkinson’s Disease

“Modern” medicine and pharmacology require an effective medical drug with a single compound for a specific disease. This seams very scientific but usually has unavoidable side effects. For example, the chemical therapy to cancer can totally damage the immunological ability of the patient leading to death early than non-treatment. On the other hand, natural antioxidant drugs not only can cure the disease but also can enhance the immunological ability of the patient leading to healthier though they usually have several compounds or a mixture. For the degenerative disease such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), natural antioxidant drugs are suitable drugs, because the pathogenesis of these diseases is complex with many targets and pathways. These effects are more evidence when the clinic trial is for long term treatment. The author reviews the studies on the protecting effects of natural antioxidants on neurons in neurodegenerative diseases, especially summarized the results about protective effect of green tea polyphenols on neurons against apoptosis of cellular and animal PD models, and of genestine and nicotine on neurons against Aβ—induced apoptosis of hippocampal neuronal and transgenic mouse AD models. Special issue in honor of Dr. Akitane Mori.     

The cerebral proteopathies

The abnormal assembly and deposition of specific proteins in the brain is the probable cause of most neurodegenerative disease afflicting the elderly. These “cerebral proteopathies” include Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), prion diseases, and a variety of other disorders. Evidence is accumulating that the anomalous aggregation of the proteins, and not a loss of protein function, is central to the pathogenesis of these diseases. Thus, therapeutic strategies that reduce the production, accumulation, or polymerization of pathogenic proteins might be applicable to a wide range of some of the most devastating diseases of old age.     

Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia

The abnormal aggregation of proteins into fibrillar lesions is a neuropathological hallmark of several sporadic and hereditary neurodegenerative diseases. For example, Lewy bodies (LBs) are intracytoplasmic filamentous inclusions that accumulate primarily in subcortical neurons of patients with Parkinson's disease (PD), or predominantly in neocortical neurons in a subtype of Alzheimer's disease (AD) known as the LB variant of AD (LBVAD) and in dementia with LBs (DLB). Aggregated neurofilament subunits and alpha-synuclein are major protein components of LBs, and these inclusions may contribute mechanistically to the degeneration of neurons in PD, DLB and LBVAD. Here we review recent studies of the protein building blocks of LBs, as well as the role LBs play in the onset and progression of PD, DLB and LBVAD. Increased understanding of the protein composition and pathological significance of LBs may provide insight into mechanisms of neuron dysfunction and death in other neurodegenerative disorders characterized by brain lesions containing massive deposits of proteinacious fibrils.     

Transition metal abnormalities in progressive dementias

Abnormal distributions of transition metals inside the brain are potential diagnostic markers for several central nervous system diseases, including Alzheimer’s disease (AD), Parkinson’s disease, dementia with Lewy bodies (DLB), bipolar disorders and depression. To further explore this possibility, the total concentrations of iron, zinc, copper, manganese, aluminum, chromium and cadmium were measured in post-mortem hippocampus and amygdala tissues taken from AD, DLB and Control patients. A statistically significant near fifty percent reduction in the total copper levels of AD patients was observed in both the hippocampus and amygdala. The statistical power of the hippocampus and amygdala copper analysis was found to be 86 and 74% respectively. No statistically significant deviations in the total metal concentrations were found for zinc, manganese, chromium or aluminum. Iron was found to be increased by 38% in AD amygdala tissues, but was unchanged in AD hippocampus tissues. Accounting for differences in tissue water content, as a function of both tissue type and disease state, revealed more consistencies with previous literature. To aid in the design of future experiments, the effect sizes for all tissue types and metals studied are also presented.     

Symposium 3: Function and Pathogenesis in Parkinson’s Disease. Synuclein: the third amyloid in Alzheimer's disease

A dramatic paradigm shift in understanding Parkinson's disease (PD) has emerged with implications for Alzheimer's disease (AD) because: (1) Mutations in the alpha‐synuclein (AS) gene cause familial PD, (2) Antibodies to AS detect Lewy bodies (LBs) and dystrophic Lewy neurites in PD, dementia with LBs (DLB), sporadic AD and the LB variant of AD (LBVAD), (3) Insoluble AS filaments are recovered from DLB brains and purified LBs, (4) Recombinant AS assembles into LB‐like filaments and residues 71–82 are essential for filament assembly, (5) AS transgenic mice and flies develop a PD‐like phenotype, (6) Cortical LBs detected with antibodies to AS correlate with dementia in PD, DLB and LBVAD, (7) Antibodies to AS detect LBs in 50% of familial AD, sporadic AD and Down's syndrome brains, (8) AS forms glial cytoplasmic inclusions (GCIs) in multiple system atrophy, (9) Epitopes throughout AS in LBs and GCIs, (10) Filamentous AS aggregates in LBs, GCIs and related lesions contain nitrated tyrosines, (11) Cells transfected with AS and treated with nitric oxide generators develop LB‐like AS inclusions, (12) Bigenic mice overexpressing mutant human APP and AS show an augmentation in AS inclusions. Thus, neurodegenerative diseases characterized by AS pathologies are synucleinopathies, and the filamentous AS lesions in these disorders may result in part from oxidative/nitrative damage to AS. Abnormal interactions of brain proteins may underlie synucleinopathies and other neurodegenerative disorders. Acknowledgements: Supported by NIA/NIH and Alzheimer's Association.     

Environmental toxins and α-synuclein in Parkinson’s disease

In recent years, environmental influences have been thought to play an important role in Parkinson’s disease (PD). Evidence from epidemiological investigations suggests that environmental factors might take part in the disease process. Intriguingly, most of environmental toxins share the common mechanism of causing mitochondria dysfunction by inhibiting complex I and promoting α-synuclein aggregation, a key factor in PD. Therefore, understanding the mechanism of interactions between α-synuclein and environmental factors could lead to new therapeutic approaches to PD.     

Cell death pathways in Parkinson’s disease: proximal triggers, distal effectors, and final steps

Parkinson’s disease (PD) is a common neurodegenerative disorder. Neuronal cell death in PD is still poorly understood, despite a wealth of potential pathogenic mechanisms and pathways. Defects in several cellular systems have been implicated as early triggers that start cells down the road toward neuronal death. These include abnormal protein accumulation, particularly of alpha-synuclein; altered protein degradation via multiple pathways; mitochondrial dysfunction; oxidative stress; neuroinflammation; and dysregulated kinase signaling. As dysfunction in these systems mounts, pathways that are more explicitly involved in cell death become recruited. These include JNK signaling, p53 activation, cell cycle re-activation, and signaling through bcl-2 family proteins. Eventually, neurons become overwhelmed and degenerate; however, even the mechanism of final cell death in PD is still unsettled. In this review, we will discuss cell death triggers and effectors that are relevant to PD, highlighting important unresolved issues and implications for the development of neuroprotective therapies.     

Interaction between parkin and alpha-synuclein

A dramatic paradigm shift in understanding Parkinson's disease (PD) has emerged with implications for Alzheimer's disease (AD) because: (1) Mutations in the alpha-synuclein (AS) gene cause familial PD, (2) Antibodies to AS detect Lewy bodies (LBs) and dystrophic Lewy neurites in PD, dementia with LBs (DLB), sporadic AD and the LB variant of AD (LBVAD), (3) Insoluble AS filaments are recovered from DLB brains and purified LBs, (4) Recombinant AS assembles into LB-like filaments and residues 71–82 are essential for filament assembly, (5) AS transgenic mice and flies develop a PD-like phenotype, (6) Cortical LBs detected with antibodies to AS correlate with dementia in PD, DLB and LBVAD, (7) Antibodies to AS detect LBs in 50% of familial AD, sporadic AD and Down's syndrome brains, (8) AS forms glial cytoplasmic inclusions (GCIs) in multiple system atrophy, (9) Epitopes throughout AS in LBs and GCIs, (10) Filamentous AS aggregates in LBs, GCIs and related lesions contain nitrated tyrosines, (11) Cells transfected with AS and treated with nitric oxide generators develop LB-like AS inclusions, (12) Bigenic mice overexpressing mutant human APP and AS show an augmentation in AS inclusions. Thus, neurodegenerative diseases characterized by AS pathologies are synucleinopathies, and the filamentous AS lesions in these disorders may result in part from oxidative/nitrative damage to AS. Abnormal interactions of brain proteins may underlie synucleinopathies and other neurodegenerative disorders. Acknowledgements:
Supported by NIA/NIH and Alzheimer's Association.     

Early calcium dysregulation in Alzheimer’s disease: setting the stage for synaptic dysfunction

Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder with no known cure or clear understanding of the mechanisms involved in the disease process. Amyloid plaques, neurofibrillary tangles and neuronal loss, though characteristic of AD, are late stage markers whose impact on the most devastating aspect of AD, namely memory loss and cognitive deficits, are still unclear. Recent studies demonstrate that structural and functional breakdown of synapses may be the underlying factor in AD-linked cognitive decline. One common element that presents with several features of AD is disrupted neuronal calcium signaling. Increased intracellular calcium levels are functionally linked to presenilin mutations, ApoE4 expression, amyloid plaques, tau tangles and synaptic dysfunction. In this review, we discuss the role of AD-linked calcium signaling alterations in neurons and how this may be linked to synaptic dysfunctions at both early and late stages of the disease.     

Modulation of α-Synuclein Aggregation by Dopamine: A Review

Parkinson’s disease (PD) is a progressive neurodegenerative disorder that is characterized by (1) the selective loss of dopaminergic neurons in the substantia nigra and (2) the deposition of misfolded α-synuclein (α-syn) as amyloid fibrils in the intracellular Lewy bodies in various region of the brain. Current thinking suggests that an interaction between α-syn and dopamine (DA) leads to the selective death of neuronal cells and the accumulation of misfolded α-syn. However, the exact mechanism by which this occurs is not fully defined. DA oxidation could play a key role is the pathogenesis of PD by causing oxidative stress, mitochondria dysfunction and impairment of protein metabolism. Here, we review the literature on the role of DA and its oxidative intermediates in modulating the aggregation pathways of α-syn.     

Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin

Normal cellular functions of hamartin and tuberin, encoded by the TSC1 and TSC2 tumor suppressor genes, are closely related to their direct interactions. However, the regulation of the hamartin-tuberin complex in the context of the physiologic role as tumor suppressor genes has not been documented. Here we show that insulin or insulin growth factor (IGF) 1 stimulates phosphorylation of tuberin, which is inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the mitogen-activated protein kinase inhibitor PD98059. Expression of constitutively active PI3K or active Akt, including Akt1 and Akt2, induces tuberin phosphorylation. We further demonstrate that Akt/PKB associates with hamartin-tuberin complexes, promoting phosphorylation of tuberin and increased degradation of hamartin-tuberin complexes. The ability to form complexes, however, is not blocked. Akt also inhibits tuberin-mediated degradation of p27(kip1), thereby promoting CDK2 activity and cellular proliferation. Our results indicate that tuberin is a direct physiological substrate of Akt and that phosphorylation of tuberin by PI3K/Akt is a major mechanism controlling hamartin-tuberin function.     

Aberrant regulation of choline metabolism by mitochondrial electron transport system inhibition in neuroblastoma cells

Anomalous choline metabolic patterns have been consistently observed in vivo using Magnetic Resonance Spectroscopy (MRS) analysis of patients with neurodegenerative diseases and tissues from cancer patient. It remains unclear; however, what signaling events may have triggered these choline metabolic aberrancies. This study investigates how changes in choline and phospholipid metabolism are regulated by distinct changes in the mitochondrial electron transport system (ETS). We used specific inhibitors to down regulate the function of individual protein complexes in the ETS of SH-SY5Y neuroblastoma cells. Interestingly, we found that dramatic elevation in the levels of phosphatidylcholine metabolites could be induced by the inhibition of individual ETS complexes, similar to in vivo observations. Such interferences produced divergent metabolic patterns, which were distinguishable via principal component analysis of the cellular metabolomes. Functional impairments in ETS components have been reported in several central nervous system (CNS) diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD); however, it remains largely unknown how the suppression of individual ETS complex function could lead to specific dysfunction in different cell types, resulting in distinct disease phenotypes. Our results suggest that the inhibition of each of the five ETS complexes might differentially regulate phospholipase activities within choline metabolic pathways in neuronal cells, which could contribute to the overall understanding of mitochondrial diseases. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Neuroprotective effects of treadmill exercise on BDNF and PI3-K/Akt signaling pathway in the cortex of transgenic mice model of Alzheimer’s disease

(AD). Although physical exercise and AD have received attention in the scientific literature, the mechanism through which treadmill exercise may impact the brain insulin signaling of AD has not been elucidated. This study aimed to evaluate the neuroprotective effects of treadmill exercise on apoptotic factors (Bcl-2/Bax ratio, caspase-3), HSP70, COX-2, BDNF and PI3-K/Akt signaling pathway in the cortex of NSE/hPS2m transgenic mice model of AD. Treadmill exercise ameliorated cognitive function in water maze test and significantly increased the level of Bcl-2/Bax ratio and HSP-70 in Tg-exe group compared to Tg-con group; on the other hand, it significantly decreased the expression of caspase-3 and COX-2 in Tg-exe group compared to Tg-con group. In addition, treadmill exercise significantly increased the expression of BDNF and PI3K/Akt in Tg-exe group compared to Tg-con group. Consequently, treadmill exercise improves cognitive function possibly via activating neurotrophic factor, BDNF and PI3k/Akt signaling pathway, and Aβ-induced neuronal cell death in the cortex of Tg mice was markedly suppressed following treadmill exercise. These results suggest that treadmill exercise may be beneficial in preventing or treating Alzheimer’s disease.     

Tuberin – A New Molecular Target in Alzheimer’s Disease?

Tuberous sclerosis complex (TSC) is a common genetic disorder in which affected individuals develop mental retardation, developmental brain defects and seizures. The TSC gene products, hamartin and tuberin, form a complex, of which tuberin is assumed to be the functional component being involved in a wide variety of different cellular processes. Here we report that tuberin protein levels are decreased in the frontal cortex of patients with Alzheimer’s disease. In addition, tuberin levels are also decreased in Down syndrome brain samples positive for β-amyloid plaques and neurofibrillary tangles. Analysis of NeuN revealed that this regulation is not a consequence of differences in the amount of postmitotic neurons. This first connection of tuberin to another common disease beside TSC stimulates new approaches to investigate the molecular development and to establish new therapeutic strategies.     

Amino acids variations in Amyloid-β peptides,mitochondrial dysfunction,and new therapies for Alzheimer’s disease

Soluble oligomers and/or aggregates of Amyloid-β (Aβ) are viewed by many as the principal cause for neurodegeneration in Alzheimer’s disease (AD). However, the mechanism by which Aβ and its aggregates cause neurodegeneration is not clear. The toxicity of Aβ has been attributed to its hydrophobicity. However, many specific mitochondrial cytopathologies e.g., loss of complex IV, loss of iron homeostasis, or oxidative damage cannot be explained by Aβ’s hydrophobicity. In order to understand the role of Aβ in these cytopathologies we hypothesized that Aβ impairs specific metabolic pathways. We focused on heme metabolism because it links iron, mitochondria, and Aβ. We generated experimental evidence showing that Aβ alters heme metabolism in neuronal cells. Furthermore, we demonstrated that Aβ binds to and depletes intracellular regulatory heme (forming an Aβ-heme complex), which provides a strong molecular connection between Aβ and heme metabolism. We showed that heme depletion leads to key cytopathologies identical to those seen in AD including loss of iron homeostasis and loss of mitochondrial complex IV. Aβ-heme exhibits a peroxidase-like catalytic activity, which catalytically accelerates oxidative damage. Interestingly, the amino acids sequence of rodent Aβ (roAβ) and human Aβ (huAβ) is identical except for three amino acids within the hydrophilic region, which is also the heme-binding motif that we identified. We found that huAβ, unlike roAβ, binds heme tightly and forms a peroxidase. Although, roAβ and huAβ equally form fibrils and aggregates, rodents do not develop AD-like neuropathology. These findings led us to propose a new mechanism for mitochondrial dysfunction and huAβ’s neurotoxicity. This mechanism prompted the development of methylene blue (MB), which increased heme synthesis, complex IV, and mitochondrial function. Thus, MB may delay the onset and progression of AD and serve as a lead to develop novel drugs to treat AD.