Pathogenesis of Alzheimer's Disease: Molecular and Cellular Mechanisms

peer reviewedAlzheimer's disease is worldwide the leading cause of dementia in the elderly. Senile plaques and neurofibrillary tangles are together with neuronal loss and cortical atrophy characteristic neuropathological features of the disease. Senile plaques contain beta-amyloid (Abeta) peptide which is produced by cleavage of the amyloid precursor protein (APP) by beta- and gamma-secretases. Neurofibrillary tangles are twisted helicoidal strands of hyperphosphorylated tau protein, a microtubule-associated protein. Both pathogenic arms which we describe are interrelated and Abeta deposition seems to potentiate tau pathology. Tangle and plaque formation is influenced by various factors including reciprocal interactions, genetic factors, inflammation and reactive oxygen species. A better understanding of the cellular and molecular cascade which leads to the neuropathological lesions of Alzheimer's disease has led to novel disease-modifying treatment strategies. They yield varying, though encouraging, results and target various stages of the pathological process. Future cooperation between basic, clinical and pharmacological research should allow the development in a foreseeable future of strategies that can halt, or even prevent, this devastating disorder

Beta-blocker migraine prophylaxis affects the excitability of the visual cortex as revealed by transcranial magnetic stimulation

The objective of this study is to assess effects of beta-blocker migraine prophylaxis on cortical excitability determined by transcranial magnetic stimulation (TMS). Phosphene and motor thresholds (PT, MT) were investigated in 29 patients with migraine, in 15 of them prior to and following preventive medication with metoprolol and in 14 patients without prophylaxis. Following prophylaxis headache frequency significantly decreased (p = 0.005) and mean PT were significantly increased (51.5 ± 7.5 vs. 63.6 ± 8.4%) compared to patients without preventive treatment (53.7 ± 5.3 vs. 52.3 ± 6.3%; p = 0.040). Mean MT did not significantly differ either between groups or due to treatment. In the group of all patients, a significant inverse correlation between headache frequency and the level of PT was found (R = −0.629; p < 0.01). There was, however, no significant correlation in the subgroups of patients. We conclude that (a) clinical efficacy of beta-blocker treatment in migraine could be (at least partly) linked to its ability to modulate the excitability of the visual cortex and (b) the PT determined by TMS appears suitable to assess the effects of prophylaxis on cortical excitability in the individual patient. This may be useful in clinical trials investigating migraine preventive drugs

Sequential loss of myelin proteins during Wallerian degeneration in the human spinal cord

Axons undergo Wallerian degeneration (WD) distal to a point of injury. In the lesioned PNS, WD may be followed by successful axonal regeneration and functional recovery. However, in the lesioned mammalian CNS, there is no significant axonal regeneration. Myelin-associated proteins (MAPs) have been shown to play significant roles in preventing axonal regeneration in the CNS. Since relatively little is known about such events in human CNS pathologies, we performed an immunohistochemical investigation on the temporal changes of four MAPs during WD in post-mortem spinal cords of 22 patients who died 2 days to 30 years after either cerebral infarction or traumatic spinal cord injury. In contrast to experimental studies in rats, the loss of myelin sheaths is greatly delayed in humans and continues slowly over a number of years. However, in agreement with animal data, a sequential loss of myelin proteins was found which was dependent on their location within the myelin sheath. Myelin proteins situated on the peri-axonal membrane were the first to be lost, the time course correlating with the loss of axonal markers. Proteins located within compact myelin or on the outer myelin membrane were still detectable 3 years after injury in degenerating fibre tracts, long after the disappearance of the corresponding axons. The persistence of axon growth-inhibitory proteins such as NOGO-A in degenerating nerve fibre tracts may contribute to the maintenance of an environment that is hostile to axon regeneration, long after the initial injury. The present data highlight the importance of correlating the well documented, lesion-induced changes that take place in controlled laboratory investigations with those that take place in the clinical domai

In silico analysis of gene expression in V3a and the superior occipital gyrus. Relevance for migraine

Introduction: Visual manifestations are the most prominent non-painful features of migraine. During the last decades, visual area V3a has gathered attention of headache scientists because of its apparent implication on aura initiation, photophobia and cortical hyper-responsiveness related to visual motion perception. In this hypothesis-generating study, we performed an in silico analysis of gene expression in left V3a and the cerebral gyrus that harbours it (left superior occipital gyrus (lSOG)) searching for transcriptomic patterns that could be linked with migraine’s pathophysiology. Materials and methods: Neurotransmitter receptor gene expression levels in left V3a were extracted from validated brain mRNA expression models using a probabilistic volumetric mask of this region. The primary visual cortex and other sensory cortices (auditory, olfactory and somatosensory) were used as comparators. Genome-wide transcriptomic differences between the gyrus harbouring left V3a (lSOG) and the rest of the cerebral cortex were assessed using the Allen Brain Institute Human RNA micro array atlas/database. Results: Adrenergic receptor β1, dopaminergic receptor D3 and serotoninergic receptors 1B, 1F and 2A, which have been previously implicated in migraine’s pathophysiology and/or treatment, showed significantly higher expression levels on left V3a. Transcriptomic differences between the lSOG harbouring V3a and the rest of the cortex comprise genes whose products are involved in neuronal excitability (SLC17A6, KCNS1, KCNG1 and GABRQ), activation of multiple signal transduction pathways (MET) and cell metabolism (SPHKAP via its interaction with cAMP-dependent protein kinase). Conclusions: Focal gene expression analysis of V3a suggests some clues about its implication in migraine. Further studies are warranted

Isotope or mass encoding of combinatorial libraries

Background: Combinatorial chemistry using solid-phase synthesis is a rapidly developing technology that can result in a significant reduction in the time required to find and optimize lead compounds. The application of this approach to traditional medicinal chemistry has led to the construction of libraries of small organic molecules on resin beads. A major difficulty in developing large combinatorial libraries is the lack of a facile encoding and decoding methodology to identify active compounds.Results: Several encoding schemes are described which use the ability of mass spectrometry to ascertain isotopic distributions. Molecular tags are attached to resin beads in parallel or on the linker used for chemical library synthesis. The tags are encoded via a controlled ratio of a number of stable isotopes on the tagging molecules, and range from a single to a complex isotopic distribution.Conclusions: A novel coding scheme is described that is useful for the generation of large encoded combinatorial libraries. The code can be cleaved after assay and analyzed by mass spectrometry in an automated fashion. An important element of the combinatorial discovery process is the ability to extract the structure-activity relationship (SAR) information made available by library screening. The speed and sensitivity of the mass-encoding scheme has the potential to determine the full SAR for a given library

Benzylmorpholine analogs as selective inhibitors of lung cytochrome P450 2A13 for the chemoprevention of lung cancer in tobacco users

Purpose: 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Methods: Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is a major challenge in compound design. Results: A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Conclusions: Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure

Visual evoked potentials in subgroups of migraine with aura patients

Background: Patients suffering from migraine with aura can have either pure visual auras or complex auras with sensory disturbances and dysphasia, or both. Few studies have searched for possible pathophysiological differences between these two subgroups of patients. Methods: Methods - Forty-seven migraine with aura patients were subdivided in a subgroup with exclusively visual auras (MA, N = 27) and another with complex neurological auras (MA+, N = 20). We recorded pattern-reversal visual evoked potentials (VEP: 15 min of arc cheques, 3.1 reversal per second, 600 sweeps) and measured amplitude and habituation (slope of the linear regression line of amplitude changes from the 1st to 6th block of 100 sweeps) for the N1-P1 and P1-N2 components in patients and, for comparison, in 30 healthy volunteers (HV) of similar age and gender distribution. Results: VEP N1-P1 habituation, i.e. amplitude decrement between 1st and 6th block, which was obvious in most HV (mean slope −0.50), was deficient in both MA (slope +0.01, p = 0.0001) and MA+ (−0.0049, p = 0.001) patients. However, VEP N1-P1 amplitudes across blocks were normal in MA patients, while they were significantly greater in MA+ patients than in HVs. Conclusions: Our findings suggest that in migraine with aura patients different aura phenotypes may be underpinned by different pathophysiological mechanisms. Pre-activation cortical excitability could be higher in patients with complex neurological auras than in those having pure visual auras or in healthy volunteers. © 2015, Coppola et al

Discovery, Synthesis, and Optimization of Diarylisoxazole-3- carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore

This is the peer reviewed version of the following article: Roy, S., Šileikytė, J., Schiavone, M., Neuenswander, B., Argenton, F., Aubé, J., … Schoenen, F. J. (2015). Discovery, Synthesis, and Optimization of Diarylisoxazole-3-carboxamides as Potent Inhibitors of the Mitochondrial Permeability Transition Pore. ChemMedChem, 10(10), 1655–1671. http://doi.org/10.1002/cmdc.201500284, which has been published in final form at doi.org/10.1002/cmdc.201500284. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The mitochondrial permeability transition pore (mtPTP) is a Ca2+-requiring mega-channel which, under pathological conditions, leads to the deregulated release of Ca2+ and mitochondrial dysfunction, ultimately resulting in cell death. Although the mtPTP is a potential therapeutic target for many human pathologies, its potential as a drug target is currently unrealized. Herein we describe an optimization effort initiated around hit 1, 5-(3-hydroxyphenyl)-N-(3,4,5-trimethoxyphenyl)isoxazole-3-carboxamide, which was found to possess promising inhibitory activity against mitochondrial swelling (EC50 100 µm). This enabled the construction of a series of picomolar mtPTP inhibitors that also potently increase the calcium retention capacity of the mitochondria. Finally, the therapeutic potential and in vivo efficacy of one of the most potent analogues, N-(3-chloro-2-methylphenyl)-5-(4-fluoro-3-hydroxyphenyl)isoxazole-3-carboxamide (60), was validated in a biologically relevant zebrafish model of collagen VI congenital muscular dystrophies

Short-latency afferent inhibition and somato-sensory evoked potentials during the migraine cycle: surrogate markers of a cycling cholinergic thalamo-cortical drive?

BACKGROUND: Short-latency afferent inhibition (SAI) consists of motor cortex inhibition induced by sensory afferents and depends on the excitatory effect of cholinergic thalamocortical projections on inhibitory GABAergic cortical networks. Given the electrophysiological evidence for thalamo-cortical dysrhythmia in migraine, we studied SAI in migraineurs during and between attacks and searched for correlations with somatosensory habituation, thalamocortical activation, and clinical features. METHODS: SAI was obtained by conditioning the transcranial magnetic stimulation-induced motor evoked potential (MEP) with an electric stimulus on the median nerve at the wrist with random stimulus intervals corresponding to the latency of individual somatosensory evoked potentials (SSEP) N20 plus 2, 4, 6, or 8\u2009ms. We recruited 30 migraine without aura patients, 16 between (MO), 14 during an attack (MI), and 16 healthy volunteers (HV). We calculated the slope of the linear regression between the unconditioned MEP amplitude and the 4-conditioned MEPs as a measure of SAI. We also measured SSEP amplitude habituation, and high-frequency oscillations (HFO) as an index of thalamo-cortical activation. RESULTS: Compared to HV, SAI, SSEP habituation and early SSEP HFOs were significantly reduced in MO patients between attacks, but enhanced during an attack. There was a positive correlation between degree of SAI and amplitude of early HFOs in HV, but not in MO or MI. CONCLUSIONS: The migraine cycle-dependent variations of SAI and SSEP HFOs are further evidence that facilitatory thalamocortical activation (of GABAergic networks in the motor cortex for SAI), likely to be cholinergic, is reduced in migraine between attacks, but increased ictally