Dissecting the pathological effects of human Abeta40 and Abeta42 in Drosophila: a potential model for Alzheimer's disease.
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ABSTRACT:
SUBMITTER: Iijima K
PROVIDER: S-EPMC404095 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Abeta40 and Abeta42 are peptides that adopt similar random-coil structures in solution. Abeta42, however, is significantly more neurotoxic than Abeta40 and forms amyloid fibrils much more rapidly than Abeta40. Here, mass spectrometry and ion mobility spectrometry are used to investigate a mixture of Abeta40 and Abeta42. The mass spectrum for the mixed solution shows the presence of a heterooligomer composed of equal parts of Abeta40 and Abeta42. Ion mobility results indicate that this mixed species comprises an oligomer distribution extending to tetramers. Abeta40 alone produces such a distribution, whereas Abeta42 alone produces oligomers as large as dodecamers. This indicates that Abeta40 inhibits Abeta42 oligomerization.
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Project description:The amyloid-beta 42 (Abeta42) is thought to play a central role in the pathogenesis of Alzheimer's disease (AD). However, the molecular mechanisms by which Abeta42 induces neuronal dysfunction and degeneration remain elusive. Mitochondrial dysfunctions are implicated in AD brains. Whether mitochondrial dysfunctions are merely a consequence of AD pathology, or are early seminal events in AD pathogenesis remains to be determined. Here, we show that Abeta42 induces mitochondrial mislocalization, which contributes to Abeta42-induced neuronal dysfunction in a transgenic Drosophila model. In the Abeta42 fly brain, mitochondria were reduced in axons and dendrites, and accumulated in the somata without severe mitochondrial damage or neurodegeneration. In contrast, organization of microtubule or global axonal transport was not significantly altered at this stage. Abeta42-induced behavioral defects were exacerbated by genetic reductions in mitochondrial transport, and were modulated by cAMP levels and PKA activity. Levels of putative PKA substrate phosphoproteins were reduced in the Abeta42 fly brains. Importantly, perturbations in mitochondrial transport in neurons were sufficient to disrupt PKA signaling and induce late-onset behavioral deficits, suggesting a mechanism whereby mitochondrial mislocalization contributes to Abeta42-induced neuronal dysfunction. These results demonstrate that mislocalization of mitochondria underlies the pathogenic effects of Abeta42 in vivo.
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Project description:Amyloid fibrils associated with Alzheimer's disease and a wide range of other neurodegenerative diseases have a cross beta-sheet structure, where main chain hydrogen bonding occurs between beta-strands in the direction of the fibril axis. The surface of the beta-sheet has pronounced ridges and grooves when the individual beta-strands have a parallel orientation and the amino acids are in-register with one another. Here we show that in Abeta amyloid fibrils, Met35 packs against Gly33 in the C-terminus of Abeta40 and against Gly37 in the C-terminus of Abeta42. These packing interactions suggest that the protofilament subunits are displaced relative to one another in the Abeta40 and Abeta42 fibril structures. We take advantage of this corrugated structure to design a new class of inhibitors that prevent fibril formation by placing alternating glycine and aromatic residues on one face of a beta-strand. We show that peptide inhibitors based on a GxFxGxF framework disrupt sheet-to-sheet packing and inhibit the formation of mature Abeta fibrils as assayed by thioflavin T fluorescence, electron microscopy, and solid-state NMR spectroscopy. The alternating large and small amino acids in the GxFxGxF sequence are complementary to the corresponding amino acids in the IxGxMxG motif found in the C-terminal sequence of Abeta40 and Abeta42. Importantly, the designed peptide inhibitors significantly reduce the toxicity induced by Abeta42 on cultured rat cortical neurons.
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Project description:Recent clinical studies have revealed that the serum levels of toxic hydrophobic bile acids (deoxy cholic acid, lithocholic acid [LCA], and glycoursodeoxycholic acid) are significantly higher in patients with Alzheimer's disease (AD) and amnestic mild cognitive impairment (aMCI) when compared to control subjects. The elevated serum bile acids may be the result of hepatic peroxisomal dysfunction. Circulating hydrophobic bile acids are able to disrupt the blood-brain barrier and promote the formation of amyloid-β plaques through enhancing the oxidation of docosahexaenoic acid. Hydrophobic bile acid may find their ways into the neurons via the apical sodium-dependent bile acid transporter. It has been shown that hydrophobic bile acids impose their pathological effects by activating farnesoid X receptor and suppressing bile acid synthesis in the brain, blocking NMDA receptors, lowering brain oxysterol levels, and interfering with 17β-estradiol actions such as LCA by binding to E2 receptors (molecular modelling data exclusive to this paper). Hydrophobic bile acids may interfere with the sonic hedgehog signaling through alteration of cell membrane rafts and reducing brain 24(S)-hydroxycholesterol. This article will 1) analyze the pathological roles of circulating hydrophobic bile acids in the brain, 2) propose therapeutic approaches, and 3) conclude that consideration be given to reducing/monitoring toxic bile acid levels in patients with AD or aMCI, prior/in combination with other treatments.
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Project description:Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ) in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the ?-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD.
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Project description:Aggregation and fibril formation of amyloid-beta (Abeta) peptides Abeta40 and Abeta42 are central events in the pathogenesis of Alzheimer disease. Previous studies have established the ratio of Abeta40 to Abeta42 as an important factor in determining the fibrillogenesis, toxicity, and pathological distribution of Abeta. To better understand the molecular basis underlying the pathologic consequences associated with alterations in the ratio of Abeta40 to Abeta42, we probed the concentration- and ratio-dependent interactions between well defined states of the two peptides at different stages of aggregation along the amyloid formation pathway. We report that monomeric Abeta40 alters the kinetic stability, solubility, and morphological properties of Abeta42 aggregates and prevents their conversion into mature fibrils. Abeta40, at approximately equimolar ratios (Abeta40/Abeta42 approximately 0.5-1), inhibits (> 50%) fibril formation by monomeric Abeta42, whereas inhibition of protofibrillar Abeta42 fibrillogenesis is achieved at lower, substoichiometric ratios (Abeta40/Abeta42 approximately 0.1). The inhibitory effect of Abeta40 on Abeta42 fibrillogenesis is reversed by the introduction of excess Abeta42 monomer. Additionally, monomeric Abeta42 and Abeta40 are constantly recycled and compete for binding to the ends of protofibrillar and fibrillar Abeta aggregates. Whereas the fibrillogenesis of both monomeric species can be seeded by fibrils composed of either peptide, Abeta42 protofibrils selectively seed the fibrillogenesis of monomeric Abeta42 but not monomeric Abeta40. Finally, we also show that the amyloidogenic propensities of different individual and mixed Abeta species correlates with their relative neuronal toxicities. These findings, which highlight specific points in the amyloid peptide equilibrium that are highly sensitive to the ratio of Abeta40 to Abeta42, carry important implications for the pathogenesis and current therapeutic strategies of Alzheimer disease.
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Project description:Alzheimer's Disease (AD) is a neurodegenerative disease characterized by two main pathological hallmarks: amyloid plaques and intracellular tau neurofibrillary tangles. However, a majority of studies focus on the individual pathologies and seldom on the interaction between the two pathologies. Herein, we present the longitudinal neuropathological and neurophysiological effects of a combined amyloid-tau model by hippocampal seeding of human-derived tau pathology in the APP.PS1/L166P amyloid animal model. We statistically assessed both neurophysiological and pathological changes using linear mixed modelling to determine if factors such as the age at which animals were seeded, genotype, seeding or buffer, brain region where pathology was quantified, and time-post injection differentially affect these outcomes. We report that AT8-positive tau pathology progressively develops and is facilitated by the amount of amyloid pathology present at the time of injection. The amount of AT8-positive tau pathology was influenced by the interaction of age at which the animal was injected, genotype, and time after injection. Baseline pathology-related power spectra and Higuchi Fractal Dimension (HFD) score alterations were noted in APP.PS1/L166P before any manipulations were performed, indicating a baseline difference associated with genotype. We also report immediate localized hippocampal dysfunction in the electroencephalography (EEG) power spectra associated with tau seeding which returned to comparable levels at 1 month-post-injection. Longitudinal effects of seeding indicated that tau-seeded wild-type mice showed an increase in gamma power earlier than buffer control comparisons which was influenced by the age at which the animal was injected. A reduction of hippocampal broadband power spectra was noted in tau-seeded wild-type mice, but absent in APP.PS1 animals. HFD scores appeared to detect subtle effects associated with tau seeding in APP.PS1 animals, which was differentially influenced by genotype. Notably, while tau histopathological changes were present, a lack of overt longitudinal electrophysiological alterations was noted, particularly in APP.PS1 animals that feature both pathologies after seeding, reiterating and underscoring the difficulty and complexity associated with elucidating physiologically relevant and translatable biomarkers of Alzheimer's Disease at the early stages of the disease.
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Project description:More than 100 missense mutations in presenilin 1 and 2 are associated with early-onset dominant Alzheimer disease. These proteins span the membrane several times and are ostensibly the catalytic component of the gamma-secretase complex, which is responsible for producing the amyloid beta-peptide (Abeta) that deposits in the Alzheimer brain. A common outcome of Alzheimer-associated presenilin mutations is an increase in the ratio of the more aggregation-prone 42-residue form of Abeta to the 40-residue variant, which is often referred to as a presenilin 'gain of function'. An apparent paradox is that most of these mutant presenilins have reduced proteolytic efficiency, which forms part of the counter argument that presenilin 'loss of function' can cause the neuronal dysfunction and death that lead to the disease. In this review, a unifying hypothesis is presented that puts forward a biochemical mechanism by which slower less-efficient forms of the protease can result in a greater proportion of 42-residue Abeta.
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Project description:Alzheimer's disease (AD) is the most common form of dementia. Several hypotheses have been put forward to explain the basis of disease onset and progression. Unfortunately, none of these seems to clarify the complexity of the pathogenesis. In fact, diverse and independent pathogenetic pathways can be disrupted at the same time, and each contributes to disease etiology. In recent years, researchers have begun studying biometals more deeply. A number of studies have shown that metal dyshomeostasis may enhance AD onset and progression. Specifically, different authors have hypothesized that alterations in metal metabolism are associated with an increased in metal-related oxidative stress and beta-amyloid oligomer formation and precipitation. Studies conducted in vivo, in vitro, in living patients and in silico studies have demonstrated that local and systemic defects in copper metabolism are characteristic signs of AD. This strongly supports the hypothesis that copper pathways may be disrupted by the disease. More specifically, a copper phenotype can be proposed for AD, based on defects found in genes involved in copper metabolism. In this review, we describe copper dyshomeostasis in AD patients and attempt to explain the basis of the AD copper phenotype. Dissecting copper pathways, we highlight mechanisms which may be at the basis of the disease. We also discuss various associated translation outcomes.
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Project description:BACKGROUND:Alzheimer's disease (AD) is characterized by physiologically endogenous proteins amyloid beta (A?) and tau undergoing a conformational change and accumulating as soluble oligomers and insoluble aggregates. Tau and A? soluble oligomers, which contain extensive ?-sheet secondary structure, are thought to be the most toxic forms. The objective of this study was to determine the ability of TWF9, an anti-?-sheet conformation antibody (a?ComAb), to selectively recognize pathological A? and phosphorylated tau in AD human tissue compared with cognitively normal age-matched controls and to improve the performance of old 3xTg-AD mice with advanced pathology in behavioral testing after acute treatment with TWF9. METHODS:In this study, we used immunohistochemistry, immunoprecipitation, and enzyme-linked immunosorbent assay (ELISA) to characterize TWF9 specificity. We further assessed cognitive performance in old (18-22 months) 3xTg-AD mice using both a Barnes maze and novel object recognition after intraperitoneal administration of TWF9 (4 mg/kg) biweekly for 2 weeks before the start of behavioral testing. Injections continued for the duration of the behavioral testing, which lasted 2 weeks. RESULTS:Histological analysis of TWF9 in formalin-fixed paraffin-embedded human control and AD (ABC score: A3B3C3) brain tissue revealed preferential cytoplasmic immunoreactivity in neurons in the AD tissue compared with controls (p?<?0.05). Furthermore, ELISA using oligomeric and monomeric A? showed a preferential affinity for oligomeric A?. Immunoprecipitation studies showed that TWF9 extracted both phosphorylated tau (p?<?0.01) and A? (p?<?0.01) from fresh frozen brain tissues. Results show that treated old 3xTg-AD mice have an enhanced novel object recognition memory (p?<?0.01) and Barnes maze performance (p?=?0.05) compared with control animals. Overall plaque burden, neurofibrillary tangles, microgliosis, and astrocytosis remained unchanged. Soluble phosphorylated tau was significantly reduced in TWF9-treated mice (p?<?0.05), and there was a trend for a reduction in soluble A? levels in the brain homogenates of female 3xTg-AD mice (p?=?0.06). CONCLUSIONS:This study shows that acute treatment with an a?ComAb can effectively improve performance in behavioral testing without reduction of amyloid plaque burden, and that peripherally administered IgG can affect levels of pathological species in the brain.
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