Erik S. Musiek

Three dimensions of the amyloid hypothesis: time, space and 'wingmen'

The amyloid hypothesis, which has been the predominant framework for research in Alzheimers disease (AD), has been the source of considerable controversy. The amyloid hypothesis postulates that amyloid-β peptide (Aβ) is the causative agent in AD. It is strongly supported by data from rare autosomal dominant forms of AD. However, the evidence that Aβ causes or contributes to age-associated sporadic AD is more complex and less clear, prompting criticism of the hypothesis. We provide an overview of the major arguments for and against the amyloid hypothesis. We conclude that Aβ likely is the key initiator of a complex pathogenic cascade that causes AD. However, we argue that Aβ acts primarily as a trigger of other downstream processes, particularly tau aggregation, which mediate neurodegeneration. Aβ appears to be necessary, but not sufficient, to cause AD. Its major pathogenic effects may occur very early in the disease process.

Quantification of F2-isoprostanes as a biomarker of oxidative stress

Oxidant stress has been implicated in a wide variety of disease processes. One method to quantify oxidative injury is to measure lipid peroxidation. Quantification of a group of prostaglandin F2α-like compounds derived from the nonezymatic oxidation of arachidonic acid, termed the F2-isoprostanes (F2-IsoPs), provides an accurate assessment of oxidative stress both in vitro and in vivo. In fact, in a recent independent study sponsored by the National Institutes of Health (NIH), F2-IsoPs were shown to be the most reliable index of in vivo oxidant stress when compared against other well known biomarkers. This protocol details our laboratorys method to quantify F2-IsoPs in biological fluids and tissues using gas chromatography-mass spectrometry (GC-MS). This procedure can be completed for 12–15 samples in 6–8 h.

F2-Isoprostanes as markers of oxidative stress in vivo : An overview

Abstract The isoprostanes are a unique series of prostaglandin-like compounds formed in vivo via a non-enzymatic mechanism involving the free radical-initiated peroxidation of arachidonic acid. This article summarizes selected aspects regarding current knowledge of these compounds and their value as markers of oxidative injury. Novel aspects related to the biochemistry of isoprostane formation are discussed and methods by which these compounds can be analysed and quantified are summarized. A considerable portion of this article examines the utility of F2-isoprostanes as markers of oxidant injury in vivo. Numerous studies carried out over the past decade have shown that these compounds are extremely accurate measures of lipid peroxidation and have illuminated the role of oxidant injury in a number of human diseases including atherosclerosis, Alzheimers disease and pulmonary disorders.

Voxel-level comparison of arterial spin-labeled perfusion MRI and FDG-PET in Alzheimer disease.

Objective: We compared the ability of arterial spin labeling (ASL), an MRI method that measures cerebral blood flow (CBF), to that of FDG-PET in distinguishing patients with Alzheimer disease (AD) from healthy, age-matched controls. Methods: Fifteen patients with AD (mean age 72 ± 6 years, Mini-Mental State Examination score [MMSE] 20 ± 6) and 19 age-matched controls (mean age 68 ± 6 years, MMSE 29 ± 1) underwent structural MRI. Participants were injected with 5 mCi of FDG during pseudocontinuous ASL scan, which was followed by PET scanning. Statistical parametric mapping and regions of interest (ROI) analysis were used to compare the ability of the 2 modalities in distinguishing patients from controls. Similarity between the 2 modalities was further assessed with linear correlation maps of CBF and metabolism to neuropsychological test scores. Results: Good agreement between hypoperfusion and hypometabolism patterns was observed, with overlap primarily in bilateral angular gyri and posterior cingulate. ROI results showed similar scales of functional deficit between patients and controls in both modalities. Both ASL and FDG-PET were able to distinguish neural networks associated with different neuropsychological tests with good overlap between modalities. Conclusions: Our voxel-wise results indicated that ASL-MRI provides largely overlapping information with FDG-PET. ROI analysis demonstrated that both modalities detected similar degrees of functional deficits in affected areas. Given its ease of acquisition and noninvasiveness, ASL-MRI may be an appealing alternative for AD studies.

Circadian clock proteins regulate neuronal redox homeostasis and neurodegeneration

Brain aging is associated with diminished circadian clock output and decreased expression of the core clock proteins, which regulate many aspects of cellular biochemistry and metabolism. The genes encoding clock proteins are expressed throughout the brain, though it is unknown whether these proteins modulate brain homeostasis. We observed that deletion of circadian clock transcriptional activators aryl hydrocarbon receptor nuclear translocator-like (Bmal1) alone, or circadian locomotor output cycles kaput (Clock) in combination with neuronal PAS domain protein 2 (Npas2), induced severe age-dependent astrogliosis in the cortex and hippocampus. Mice lacking the clock gene repressors period circadian clock 1 (Per1) and period circadian clock 2 (Per2) had no observed astrogliosis. Bmal1 deletion caused the degeneration of synaptic terminals and impaired cortical functional connectivity, as well as neuronal oxidative damage and impaired expression of several redox defense genes. Targeted deletion of Bmal1 in neurons and glia caused similar neuropathology, despite the retention of intact circadian behavioral and sleep-wake rhythms. Reduction of Bmal1 expression promoted neuronal death in primary cultures and in mice treated with a chemical inducer of oxidative injury and striatal neurodegeneration. Our findings indicate that BMAL1 in a complex with CLOCK or NPAS2 regulates cerebral redox homeostasis and connects impaired clock gene function to neurodegeneration.

Electrophilic Cyclopentenone Neuroprostanes Are Anti-inflammatory Mediators Formed from the Peroxidation of the ω-3 Polyunsaturated Fatty Acid Docosahexaenoic Acid

The ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) possesses potent anti-inflammatory properties and has shown therapeutic benefit in numerous inflammatory diseases. However, the molecular mechanisms of these anti-inflammatory properties are poorly understood. DHA is highly susceptible to peroxidation, which yields an array of potentially bioactive lipid species. One class of compounds are cyclopentenone neuroprostanes (A4/J4-NPs), which are highly reactive and similar in structure to anti-inflammatory cyclopentenone prostaglandins. Here we show that a synthetic A4/J4-NP, 14-A4-NP (A4-NP), potently suppresses lipopolysaccharideinduced expression of inducible nitric-oxide synthase and cyclooxygenase-2 in macrophages. Furthermore, A4-NP blocks lipopolysaccharide-induced NF-κB activation via inhibition of Iκ kinase-mediated phosphorylation of IκBα. Mutation on Iκ kinase β cysteine 179 markedly diminishes the effect of A4-NP, suggesting that A4-NP acts via thiol modification at this residue. Accordingly, the effects of A4-NP are independent of peroxisome proliferator-activated receptor-γ and are dependent on an intact reactive cyclopentenone ring. Interestingly, free radical-mediated oxidation of DHA greatly enhances its anti-inflammatory potency, an effect that closely parallels the formation of A4/J4-NPs. Furthermore, chemical reduction or conjugation to glutathione, both of which eliminate the bioactivity of A4-NP, also abrogate the anti-inflammatory effects of oxidized DHA. Thus, we have demonstrated that A4/J4-NPs, formed via the oxidation of DHA, are potent inhibitors of NF-κB signaling and may contribute to the anti-inflammatory actions of DHA. These findings have implications for understanding the anti-inflammatory properties of ω-3 fatty acids, and elucidate novel interactions between lipid peroxidation products and inflammation.

Sleep, circadian rhythms, and the pathogenesis of Alzheimer Disease

Disturbances in the sleep–wake cycle and circadian rhythms are common symptoms of Alzheimer Disease (AD), and they have generally been considered as late consequences of the neurodegenerative processes. Recent evidence demonstrates that sleep–wake and circadian disruption often occur early in the course of the disease and may even precede the development of cognitive symptoms. Furthermore, the sleep–wake cycle appears to regulate levels of the pathogenic amyloid-beta peptide in the brain, and manipulating sleep can influence AD-related pathology in mouse models via multiple mechanisms. Finally, the circadian clock system, which controls the sleep–wake cycle and other diurnal oscillations in mice and humans, may also have a role in the neurodegenerative process. In this review, we examine the current literature related to the mechanisms by which sleep and circadian rhythms might impact AD pathogenesis, and we discuss potential therapeutic strategies targeting these systems for the prevention of AD.

Direct comparison of fluorodeoxyglucose positron emission tomography and arterial spin labeling magnetic resonance imaging in Alzheimer's disease

The utility of fluorodeoxyglucose positron emission tomography (FDG‐PET) imaging in Alzheimers disease (AD) diagnosis has been well established. Recently, measurement of cerebral blood flow using arterial spin labeling magnetic resonance imaging (ASL‐MRI) has shown diagnostic potential in AD, although it has never been directly compared with FDG‐PET.

Recent advances in the biochemistry and clinical relevance of the isoprostane pathway

Isoprostanes (IsoPs), lipid peroxidation products formed via the free radical-mediated oxidation of arachidonic acid, have become the “gold standard” biomarker of oxidative stress in vivo over the past 15 yr. Significant advances have been made in understanding this important pathway of lipid peroxidation. Recent studies from our laboratory are discussed that have provided insights into the mechanism of formation and regioisomeric distribution of these compounds and that have identified novel products of the IsoP pathway such as cyclized dioxolane IsoPs, IsoP-derived racemic prostaglandins, and reactive cyclopentenone IsoP, the latter of which possess potent biological actions. Furthermore, new independent studies have demonstrated that IsoPs are the most reliable available marker of lipid peroxidation in vivo, and recent work examining IsoP formation has provided valuable infromation about the pathogenesis of numerous human diseases. Thus, the complexity of the IsoP pathway has expanded, providing novel insights into mechanisms of lipid peroxidation in vivo and allowing investigators to explore the role of oxidative stress in human disease.

Mechanisms linking circadian clocks, sleep, and neurodegeneration

Disruptions of normal circadian rhythms and sleep cycles are consequences of aging and can profoundly affect health. Accumulating evidence indicates that circadian and sleep disturbances, which have long been considered symptoms of many neurodegenerative conditions, may actually drive pathogenesis early in the course of these diseases. In this Review, we explore potential cellular and molecular mechanisms linking circadian dysfunction and sleep loss to neurodegenerative diseases, with a focus on Alzheimer’s disease. We examine the interplay between central and peripheral circadian rhythms, circadian clock gene function, and sleep in maintaining brain homeostasis, and discuss therapeutic implications. The circadian clock and sleep can influence a number of key processes involved in neurodegeneration, suggesting that these systems might be manipulated to promote healthy brain aging.