Alzheimer Disease: Penke B

Zádori D, Datki Z, Penke B. · Szegedi Tudományegyetem, Altalános Orvostudományi Kar, Orvosi Vegytani Intézet, Szeged. · Ideggyogy Sz. · Pubmed #18198789 No free full text.

Abstract: In Alzheimer's disease, which belongs to the neurodegenerative disorders, the ethiopathogenetic role of several risk factors has been proved. A considerable number of them are mainly known as cardiovascular risk factors and can precipitate chronic brain hypoperfusion. Using functional imaging techniques, this hypoperfusion and the resulting hypometabolism become detectable in the watershed areas of the brain as early as in the stage of mild cognitive impairment. Hypoperfusion leads to the degeneration of capillaries in this area causing the deterioration of diffusion. The further reduction of nutrient and oxygen support of neurons is capable to initiate a neurodegenerative process which spreads along the glutaminergic system arising from the neurons of the association cortices. The neuropathological lesions of this neuronal system, such as the neurofibrillary tangles and the beta-amyloid plaques, are known to be the characteristic markers of Alzheimer's disease. In our review we present the development of hypoperfusion and its consequences in the watershed areas of the brain and describe the neurodegenerative process of the neuronal system arising from the neurons of the association cortices in the early stage of Alzheimer's disease. Considering the previous hypotheses and the neuropathological lesions of Alzheimer's disease we give a new consensus model to characterize the pathomechanism of the disorder.

Verdier Y, Zarándi M, Penke B. · Department of Medical Chemistry, University of Szeged, Szeged, Hungary. · J Pept Sci. · Pubmed #15160835 No free full text.

Abstract: The extracellular accumulation of amyloid-beta (Abeta) in neuritic plaques is one of the characteristic hallmarks of Alzheimer's disease (AD), a progressive dementing neurodegenerative disorder of the elderly. By virtue of its structure, Abeta is able to bind to a variety of biomolecules, including lipids, proteins and proteoglycans. The binding of the various forms of Abeta (soluble or fibrillar) to plasma membranes has been studied with regard to the direct toxicity of Abeta to neurons, and the activation of a local inflammation phase involving microglia. The binding of Abeta to membrane lipids facilitates Abeta fibrillation, which in turn disturbs the structure and function of the membranes, such as membrane fluidity or the formation of ion channels. A subset of membrane proteins binds Abeta. The serpin-enzyme complex receptor (SEC-R) and the insulin receptor can bind the monomeric form of Abeta. The alpha7nicotinic acetylcholine receptor (alpha7nAChR), integrins, RAGE (receptor for advanced glycosylation end-products) and FPRL1 (formyl peptide receptor-like 1) are able to bind the monomeric and fibrillar forms of Abeta. In addition, APP (amyloid precursor protein), the NMDA-R (N-methyl-D-aspartate receptor), the P75 neurotrophin receptor (P75NTR), the CLAC-P/collagen type XXV (collagen-like Alzheimer amyloid plaque component precursor/collagen XXV), the scavenger receptors A, BI (SR-A, SR-BI) and CD36, a complex involving CD36, alpha6beta1-integrin and CD47 have been reported to bind the fibrillar form of Abeta. Heparan sulfate proteoglycans have also been described as cell-surface binding sites for Abeta. The various effects of Abeta binding to these membrane molecules are discussed.

Verdier Y, Penke B. · Department of Medical Chemistry, University of Szeged, and Protein Chemistry Research Group of the Hungarian Academy of Science, Szeged, Hungary. · Curr Protein Pept Sci. · Pubmed #14965318 No free full text.

Abstract: The binding of amyloid beta peptides (Abeta) to plasma membranes appears to be a promising point of intervention in the events leading to the development of Alzheimer's disease (AD). This binding has been studied as regards the direct toxicity of Abeta on neurons, and the activation of a local inflammation phase involving microglia. By virtue of its structure, Abeta is able to bind to a variety of biomolecules, including lipids, proteoglycans and proteins. This review focuses on the membrane proteins that can mediate the interaction between Abeta and the plasma membranes in AD. On neurons, these are APP (amyloid precursor protein), the NMDA-R (N-methyl-D-aspartate receptor), integrins, the alpha7nicotinic acetylcholine receptor (alpha7nAChR), the P75 neurotrophin receptor (P75NTR) and the CLAC-P/collagen type XXV (collagen-like Alzheimer amyloid plaque component precursor/collagen XXV). On glial cells, FPRL1 (formyl peptide receptor-like 1), the scavenger receptors A, BI (SR-A, SR-BI) and CD36, a complex involving CD36, alpha(6)beta(1)-integrin and CD47, and heparan sulfate proteoglycans have been reported to bind Abeta. It should be noted that integrins, RAGE (receptor for advanced glycosylation end-products), the Serpin-enzyme complex receptor (SEC-R) and the insulin receptor can bind Abeta and are present on neurons and on glial cells. After a presentation of the structure and the function of each of these proteins, the method used to prove their binding to Abeta is described, and the implication of this binding in AD is discussed. Finally, it is underlined that multireceptor complexes containing integrins may be involved in this interaction.

DeMager PP, Penke B, Walter R, Harkany T, Härtignny W. · Research Group of Pharmacochemistry, Institute of Pharmacology and Toxicology, University of Leipzig, Härtelstr. 16-18, Saxony, Leipzig, D-04107, Germany. · Curr Med Chem. · Pubmed #12369886 No free full text.

Abstract: Main neuropathological hallmarks of Alzheimer's disease (AD) and other neurodegenerative disorders are the deposition of neurofibrillary tangles consisting of abnormally phosphorylated protein tau and of senile plaques largely containing insoluble beta-amyloid peptides (A beta), containing up to 43 amino acid residues derived from the beta-amyloid precursor protein. Such A beta-sheets become visible by using suitable histochemical methods. Molecular simulation showed that the central, alpha-helical, lipophilic, antigenic folding domain of the A beta-peptide loop is a promising molecular target of beta-sheet breakers that thus prevent the polymerization of A beta into aggregates. It seems that di- and tetramers of A beta-peptides have a beta-barrel- like structure. In the present review, an optimized neural network analysis was applied to recognize possible structure-activity relationships of peptidomimetic beta-sheet breakers. The anti-aggregatory potency of beta-sheet breakers largely depends upon their total, electrostatic, and hydration energy as derived from their geometry-optimized conformations using the hybrid Gasteiger-molecular mechanics approach. Moreover, we also summarize peptide misfolding in several disorders with distinct clinical symptoms, including prion diseases and a broad variety of systemic amyloidoses, as the common pathogenic step driving these disorders. In particular, conversion of nontoxic alpha-helix/random-coils to beta-sheet conformation was recognized as being critical in producing highly pathogenic peptide assemblies. Whereas conventional pharmacotherapy of AD is mainly focused on restoring cholinergic activity and diminishing inflammatory responses as a consequence of amyloid accumulation, we here survey potential approaches aimed at preventing or reserving the transition of neurotoxic peptide species from alpha-helical/random coil to beta-sheet conformation and thus abrogating their effects in a broad variety of disorders.

Härtig W, Bauer A, Brauer K, Grosche J, Hortobágyi T, Penke B, Schliebs R, Harkany T. · Department of Neurochemistry, Paul Flechsig Institute for Brain Research, University of Leipzig, Germany. · Rev Neurosci. · Pubmed #12160262 No free full text.

Abstract: Recognition of the involvement of cholinergic neurons in the modulation of cognitive functions and their severe dysfunction in neurodegenerative disorders, such as Alzheimer's disease, initiated immense research efforts aimed at unveiling the anatomical organization and cellular characteristics of the basal forebrain (BFB) cholinergic system. Concomitant with our unfolding knowledge about the structural and functional complexity of the BFB cholinergic projection system, multiple pharmacological strategies were introduced to rescue cholinergic nerve cells from noxious attacks; however, a therapeutic breakthrough is still awaited. In this review, we collected recent findings that significantly contributed to our better understanding of cholinergic functions under disease conditions, and to the design of effective means to restore lost or damaged cholinergic functions. To this end, we first provide a brief survey of the neuroanatomical organization of BFB nuclei with emphasis on major evolutionary differences among mammalian species, in particular rodents and primates, and discuss limitations of the translation of experimental data to human therapeutic applications. Subsequently, we summarize the involvement of cholinergic dysfunction in the pathogenesis of severe neurological conditions, including stroke, traumatic brain injury, virus encephalitis and Alzheimer's disease, and emphasize the critical role of pro-inflammatory cytokines as common mediators of cholinergic neuronal damage. Moreover, we review leading functional concepts on the limited recovery of cholinergic neurons and their impaired plastic re-modeling, as well as on the hampered interplay of the ascending cholinergic and monoaminergic projection systems under neurodegenerative conditions. In addition, recent advances in the dynamic labeling of living cholinergic neurons by fluorochromated antibodies, referred to as in vivo labeling, and novel neuroimaging approaches as potential diagnostic tools of progressive cholinergic decline are surveyed. Finally, the potential of cell replacement strategies using embryonic and adult stem cells, and multipotent neural progenitors, as a means to recover damaged cholinergic functions, is discussed.

Harkany T, Abrahám I, Kónya C, Nyakas C, Zarándi M, Penke B, Luiten PG. · Department of Animal Physiology, University of Groningen, Haren, The Netherlands. · Rev Neurosci. · Pubmed #11065280 No free full text.

Abstract: One of the characteristic neuropathological hallmarks of Alzheimer's disease (AD) is the extracellular accumulation of beta-amyloid peptides (Abeta) in neuritic plaques. Experimental data indicate that different molecular forms of Abeta affect a wide array of neuronal and glial functions and thereby may lead to neuronal death in the nervous system. Whereas the fatal outcome of Abeta overproduction in transgenic cell lines, and of exogenous Abeta administration in numerous neurotoxicity models, is well established, particular facets of a complex molecular cascade by which Abeta attack neural cells are still elusive. In the present review we summarize recent knowledge on mechanisms of Abeta aggregation, its role in Abeta neurotoxicity, and binding of Abeta peptides to putative neuronal and glial receptors. Additionally, an integrative view on the interactions of Ca2+ -mediated excitotoxicity and free radical-induced oxidative stress in Abeta toxicity is provided. Furthermore, we survey advances of pharmacological investigations attempting to prevent and antagonize Abeta toxicity, or to promote neuronal regeneration following Abeta-induced neurotoxic insults. We distinguish two major classes of therapeutic approaches: conventional pharmacotherapy that employs blockade of known receptors, signal transduction pathways, and re-uptake of neurotransmitters, and direct targeting of neurotoxic Abeta by means of beta-sheet breakers, functional anti-Abeta peptides, and antibodies. Although a clinically relevant neuroprotective strategy is not yet available, sequential combination of drug regimens may provide prospects for effective antagonism of late-life Abeta burden and subsequent development of dementia.

Harkany T, Penke B, Luiten PG. · Department of Animal Physiology, University of Groningen, Haren, The Netherlands. · Ann N Y Acad Sci. · Pubmed #10818528 No free full text.

Abstract: Alzheimer's disease is the most common type of dementia with a still largely unclear etiopathology. One of the factors that may directly contribute to the development and progression of the disorder is the abundant accumulation of beta-amyloid peptides (A beta) in senile plaques. In the present account we review coherent in vivo experimental evidence that A beta infusion into the rat magnocellular nucleus basalis (MBN) induces abrupt and persistent behavioral dysfunctions, perturbations of sensory information processing, storage, and retrieval. These substantial behavioral changes are due to the loss of cholinergic neurons in the MBN and their ascending projections to the frontoparietal cortex. Both neuroanatomical and neurochemical observations pin-point that infusion of A beta into the rat basal forebrain significantly decreases choline-acetyltransferase and acetylcholinesterase activities and the population of--probably--M2 muscarinic acetylcholine receptors in the cerebral cortex. Neuropharmacological data indicate that A beta toxicity is mediated by an excitotoxic cascade involving blockade of astroglial glutamate uptake, sustained activation of N-methyl-D-aspartate receptors and an overt intracellular Ca2+ influx. These changes are associated with increased nitric oxide synthase activity in cortical target areas that may directly lead to the generation of free radicals. Besides, as microvessels of the neocortex receive direct input from the MBN we assume that the loss of cholinergic innervation and hence that of tonic cholinergic vasoregulation ultimately leads to disturbances of vascular (endothelial) function and nutrient supply that may directly enhance neuronal vulnerability during aging and in Alzheimer's disease.

Harkany T, Hortobágyi T, Sasvári M, Kónya C, Penke B, Luiten PG, Nyakas C. · Central Research Division of Clinical and Experimental Laboratory Medicine, Haynal Imre University of Health Sciences, Budapest, Hungary. · Prog Neuropsychopharmacol Biol Psychiatry. · Pubmed #10621945 No free full text.

Abstract: 1. beta-Amyloid peptides (A beta s) accumulate abundantly in the Alzheimer's disease (AD) brain in areas subserving information acquisition and processing, and memory formation. A beta fragments are produced in a process of abnormal proteolytic cleavage of their precursor, the amyloid precursor protein (APP). While conflicting data exist in the literature on the roles of A beta s in the brain, and particularly in AD, recent studies have provided firm experimental evidence for the direct neurotoxic properties of A beta. 2. Sequence analysis of A beta s revealed a high degree of evolutionary conservation and inter-species homology of the A beta amino acid sequence. In contrast, synthetic A beta fragments, even if modified fluorescent or isotope-labeled derivatives, are pharmacological candidates for in vitro and in vivo modeling of their cellular actions. During the past decade, acute injection, prolonged mini-osmotic brain perfusion approaches or A beta infusions into the blood circulation were developed in order to investigate the effects of synthetic A beta s, whereas transgenic models provided insight into the distinct molecular steps of pathological APP cleavage. 3. The hippocampus, caudate putamen, amygdala and neocortex all formed primary targets of acute neurotoxicity screening, but functional consequences of A beta infusions were primarily demonstrated following either intracerebroventricular or basal forebrain (medial septum or magnocellular basal nucleus (MBN)) infusions of A beta fragments. 4. In vivo investigations confirmed that, while the active core of A beta is located within the beta(25-35) sequence, the flanking peptide regions influence not only the folding properties of the A beta fragments, but also their in vivo neurotoxic potentials. 5. It has recently been established that A beta administration deranges neuron-glia signaling, affects the glial glutamate uptake and thereby induces noxious glutamatergic stimulation of nerve cells. In fact, a critical role for N-methyl-D-aspartate (NMDA) receptors was postulated in the neurotoxic processes. Additionally, A beta s might become internalized, either after their selective binding to cell-surface receptors or after membrane association in consequence of their highly lipophilic nature, and induce free radical generation and subsequent oxidative injury. Ca(2+)-mediated neurotoxic events and generation of oxygen free radicals may indeed potentiate each other, or even converge to the same neurotoxic events, leading to cell death. 6. Neuroprotection against A beta toxicity was achieved by both pre- and post-treatment with NMDA receptor channel antagonists. Moreover, direct radical-scavengers, such as vitamin E or vitamin C, attenuated A beta toxicity with high efficacy. Interestingly, combined drug treatments did not necessarily result in additive enhanced neuroprotection. 7. Similarly to the blockade of NMDA receptors, the neurotoxic action of A beta s could be markedly decreased by pharmacological manipulation of voltage-dependent Ca(2+)-channels, serotonergic IA or adenosine A1 receptors, and by drugs eliciting membrane hyperpolarization or indirect blockade of Ca(2+)-mediated intracellular consequences of intracerebral A beta infusions. 8. A beta neurotoxicity might be dose-dependently modulated by trace metals. In spite of the fact that zinc (Zn) may act as a potent inhibitor of the NMDA receptor channel, high Zn doses accelerate A beta fibril formation, stabilize the beta-sheet conformation and thereby potentiate A beta neurotoxicity. Combined trace element supplementation with Se, Mn, or Mg, which prevails over the expression of detoxifying enzymes or counteracts intracellular elevations of Ca2+, may reduce the neurotoxic impact of A beta s. 9. Alterations in the regulatory functions of the hypothalamo-pituitary-adrenal axis may contribute significantly to neurodegenerative changes in the brain. Furthermore, AD patients exhibit substantially increased circadia

Hunya A, Földi I, Szegedi V, Soós K, Zarándi M, Szabó A, Zádori D, Penke B, Datki ZL. · Department of Medical Chemistry, University of Szeged, Szikra utca 2, Szeged, Hungary. · Brain Res Bull. · Pubmed #18355641 No free full text.

Abstract: Alpha-synuclein (alphaSN) plays a major role in numerous neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. Intracellular inclusions containing aggregated alphaSN have been reported in Alzheimer's and Parkinson's affected brains. Moreover, a proteolytic fragment of alphaSN, the so-called non-amyloid component of Alzheimer's disease amyloid (NAC) was found to be an integral part of Alzheimer's dementia related plaques. Despite the extensive research on this topic, the exact toxic mechanism of alphaSN remains elusive. We have taken the advantage of an alphaSN overexpressing SH-SY5Y cell line and investigated the effects of classical apoptotic factors (e.g. H(2)O(2), amphotericin B and ruthenium red) and aggregated disease-related peptides on cell viability compared to wild type neuroblastoma cells. It was found that alphaSN overexpressing cells are more sensitive to aggregated peptides treatment than normal expressing counterparts. In contrast, cells containing elevated amount of alphaSN were less vulnerable to classical apoptotic stressors than wild type cells. In addition, alphaSN overexpression is accompanied by altered phenotype, attenuated proliferation kinetics, increased neurite arborisation and decreased cell motility. Based on these results, the alphaSN overexpressing cell lines may represent a good and effective in vitro model for Alzheimer's and Parkinson's disease.

Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K. · Department of Neurology, University of the Saarland, Homburg, Germany. · Cell Physiol Biochem. · Pubmed #17982277 No free full text.

Abstract: Microglial activation is a key feature in Alzheimer's disease and is considered to contribute to progressive neuronal injury by release of neurotoxic products. The innate immune receptor Toll-like-receptor 4 (TLR4), localized on the surface of microglia, is a first-line host defense receptor against invading microorganisms. Here, we show that a spontaneous loss-of-function mutation in the Tlr4 gene strongly inhibits microglial and monocytic activation by aggregated Alzheimer amyloid peptide resulting in a significantly lower release of the inflammatory products IL-6, TNFalpha and nitric oxide. Treatment of primary murine neuronal cells with supernatant of amyloid peptide-stimulated microglia demonstrates that Tlr4 contributes to amyloid peptide-induced microglial neurotoxicity. In addition, stimulation experiments in transfected HEK293 cells allowed to define a tri-molecular receptor complex consisting of TLR4, MD-2 and CD14 necessary for full cellular activation by aggregated amyloid peptide. A clinical relevance of these findings is supported by a marked upregulation of Tlr4 mRNA in APP transgenic mice and by an increased expression of TLR4 in Alzheimer's disease brain tissue associated with amyloid plaque deposition. Together, these observations provide the first evidence for a role of the key innate immune receptor, TLR4, in neuroinflammation in Alzheimer's disease.

Sipos E, Kurunczi A, Kasza A, Horváth J, Felszeghy K, Laroche S, Toldi J, Párducz A, Penke B, Penke Z. · University of Szeged, Institute of Medical Chemistry, Dóm tér 8., H-6720 Szeged, Hungary. · Neuroscience. · Pubmed #17499931 No free full text.

Abstract: Alzheimer's disease is characterized by the presence of senile plaques in the brain, composed mainly of aggregated amyloid-beta peptide (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease and is a potential target for therapeutic intervention. Amyloid plaques occur in an increasing number of brain structures during the progression of the disease, with a heavy load in regions of the temporal cortex in the early phases. Here, we investigated the cognitive deficits specifically associated with amyloid pathology in the entorhinal cortex. The amyloid peptide Abeta(1-42) was injected bilaterally into the entorhinal cortex of rats and behavioral performance was assessed between 10 and 17 days after injection. We found that parameters of motor behavior in an open-field as well as spatial working memory tested in an alternation task were normal. In contrast, compared with naive rats or control rats injected with saline, rats injected with Abeta(1-42) showed impaired recognition memory in an object recognition task and delayed acquisition in a spatial reference memory task in a water-maze, despite improved performance with training in this task and normal spatial memory in a probe test given 24 h after training. This profile of behavioral deficits after injection of Abeta(1-42) into the entorhinal cortex was similar to that observed in another group of rats injected with the excitotoxic drug, N-methyl-d-aspartate. Immunohistochemical analysis after behavioral testing revealed that Abeta(1-42) injection induced a reactive astroglial response and plaque-like deposits in the entorhinal cortex. These results show that experimentally-induced amyloid pathology in the entorhinal cortex induces selective cognitive deficits, resembling those observed in early phases of Alzheimer's disease. Therefore, injection of protofibrillar-fibrillar Abeta(1-42) into the entorhinal cortex constitutes a promising animal model for investigating selective aspects of Alzheimer's disease and for screening drug candidates designed against Abeta pathology.

Hartai Z, Juhász A, Rimanóczy A, Janáky T, Donkó T, Dux L, Penke B, Tóth GK, Janka Z, Kálmán J. · Department of Psychiatry, University of Szeged, Szeged, Hungary. · Neurochem Int. · Pubmed #17023091 No free full text.

Abstract: Kynurenine aminotransferases (KAT I and KAT II) are responsible for the transamination of kynurenine (KYN) to form kynurenic acid (KYNA), an excitatory amino acid receptor antagonist. Since these members of the kynurenine pathway (KP) are proposed to be involved in the pathogenesis of Alzheimer's dementia (AD), the activities of these enzymes and the levels of these metabolites were measured in the plasma and red blood cells (RBCs) of AD and control subjects together with the inheritance of the apolipoprotein (APOE) epsilon4 allele. KYNA levels were significantly decreased both in the plasma and in the RBCs in AD, but the levels of KYN and the activities of KAT I and KAT II remained unchanged. No association has been found with the possession of the epsilon4 allele. These findings indicate an altered peripheral KP in AD regardless of the APOE status of the probands.

Oksman M, Iivonen H, Hogyes E, Amtul Z, Penke B, Leenders I, Broersen L, Lütjohann D, Hartmann T, Tanila H. · Department of Neuroscience and Neurology, University of Kuopio, Finland. · Neurobiol Dis. · Pubmed #16765602 No free full text.

Abstract: The present study assessed the influence of dietary lipids on accumulation of amyloid beta-peptide (Abeta) in the brain. Seven experimental diets with varying n-6/n-3-ratio, saturated and polyunsaturated fatty acid and cholesterol contents were fed to transgenic APPswe/PS1dE9 mice for 3-4 months beginning at a young adult age (6 months). Hippocampal Abeta levels were determined with ELISA and plaque load by using immunocytochemistry. A typical Western diet with 40% saturated fatty acids and 1% of cholesterol increased, while diets supplemented with docosahexaenoic acid (DHA) decreased Abeta levels compared to regular (soy oil based) diet. DHA diet also decreased the number of activated microglia in hippocampus and increased exploratory activity of transgenic mice, but did not improve their spatial learning in the water maze. The favorable effect of DHA on Abeta production was verified in two different cell lines. Regulation of dietary lipid intake may offer a new tool to reduce the risk of Alzheimer's disease at the population level.

Karsai A, Mártonfalvi Z, Nagy A, Grama L, Penke B, Kellermayer MS. · Department of Biophysics, University of Pécs, Faculty of Medicine, Pécs H-7624, Hungary. · J Struct Biol. · Pubmed #16713296 No free full text.

Abstract: The 39- to 42-residue-long amyloid beta-peptide (Abeta-peptide) forms filamentous structures in the neuritic plaques found in the neuropil of Alzheimer's disease patients. The assembly and deposition of Abeta-fibrils is one of the most important factors in the pathogenesis of this neurodegenerative disease. Although the structural analysis of amyloid fibrils is difficult, single-molecule methods may provide unique insights into their characteristics. In the present work, we explored the nanomechanical properties of amyloid fibrils formed from the full-length, most neurotoxic Abeta1-42 peptide, by manipulating individual fibrils with an atomic force microscope. We show that Abeta-subunit sheets can be mechanically unzipped from the fibril surface with constant forces in a reversible transition. The fundamental unzipping force (approximately 23 pN) was significantly lower than that observed earlier for fibrils formed from the Abeta1-40 peptide (approximately 33 pN), suggesting that the presence of the two extra residues (Ile and Ala) at the peptide's C-terminus result in a mechanical destabilization of the fibril. Deviations from the constant force transition may arise as a result of geometrical constraints within the fibril caused by its left-handed helical structure. The nanomechanical fingerprint of the Abeta1-42 is further influenced by the structural dynamics of intrafibrillar interactions.

Shemer I, Holmgren C, Min R, Fülöp L, Zilberter M, Sousa KM, Farkas T, Härtig W, Penke B, Burnashev N, Tanila H, Zilberter Y, Harkany T. · Department of Neuroscience, Retzius väg 8:A3-417, Karolinska Institutet, S-17177 Stockholm, Sweden. · Eur J Neurosci. · Pubmed #16630051 No free full text.

Abstract: Cognitive decline in Alzheimer's disease (AD) stems from the progressive dysfunction of synaptic connections within cortical neuronal microcircuits. Recently, soluble amyloid beta protein oligomers (Abeta(ol)s) have been identified as critical triggers for early synaptic disorganization. However, it remains unknown whether a deficit of Hebbian-related synaptic plasticity occurs during the early phase of AD. Therefore, we studied whether age-dependent Abeta accumulation affects the induction of spike-timing-dependent synaptic potentiation at excitatory synapses on neocortical layer 2/3 (L2/3) pyramidal cells in the APPswe/PS1dE9 transgenic mouse model of AD. Synaptic potentiation at excitatory synapses onto L2/3 pyramidal cells was significantly reduced at the onset of Abeta pathology and was virtually absent in mice with advanced Abeta burden. A decreased alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/N-methyl-D-aspartate (NMDA) receptor-mediated current ratio implicated postsynaptic mechanisms underlying Abeta synaptotoxicity. The integral role of Abeta(ol)s in these processes was verified by showing that pretreatment of cortical slices with Abeta((25-35)ol)s disrupted spike-timing-dependent synaptic potentiation at unitary connections between L2/3 pyramidal cells, and reduced the amplitude of miniature excitatory postsynaptic currents therein. A robust decrement of AMPA, but not NMDA, receptor-mediated currents in nucleated patches from L2/3 pyramidal cells confirmed that Abeta(ol)s perturb basal glutamatergic synaptic transmission by affecting postsynaptic AMPA receptors. Inhibition of AMPA receptor desensitization by cyclothiazide significantly increased the amplitude of excitatory postsynaptic potentials evoked by afferent stimulation, and rescued synaptic plasticity even in mice with pronounced Abeta pathology. We propose that soluble Abeta(ol)s trigger the diminution of synaptic plasticity in neocortical pyramidal cell networks during early stages of AD pathogenesis by preferentially targeting postsynaptic AMPA receptors.

Karsai A, Nagy A, Kengyel A, Mártonfalvi Z, Grama L, Penke B, Kellermayer MS. · Department of Biophysics, University of Pécs, Faculty of Medicine, Pécs, H-7624 Hungary. · J Chem Inf Model. · Pubmed #16309267 No free full text.

Abstract: Amyloid fibrils are self-associating filamentous structures formed from the 39- to 42-residue-long amyloid beta peptide (Abeta peptide). The deposition of Abeta fibrils is one of the most important factors in the pathogenesis of Alzheimer's disease. Abeta25-35 is a fibril-forming peptide that is thought to represent the biologically active, toxic form of the full-length Abeta peptide. We have recently shown that beta sheets can be mechanically unzipped from the fibril surface with constant forces in a reversible transition, and the unzipping forces differ in fibrils composed of different peptides. In the present work, we explored the effect of epsilon-amino acetylation of the Lys28 residue on the magnitude of the unzipping force of Abeta25-35 fibrils. Although the gross structure of the Lys28-acetylated (Abeta25-35_K28Ac) and wild-type Abeta25-35 (Abeta25-35wt) fibrils were similar, as revealed by atomic force microscopy, the fundamental unzipping forces were significantly lower for Abeta25-35_K28Ac (20 +/- 4 pN SD) than for Abeta25-35wt (42 +/- 9 pN SD). Simulations based on a simple two-state model suggest that the decreased unzipping forces, caused most likely by steric constraints, are likely due to a destabilized zippered state of the fibril.

Zana M, Juhász A, Rimanóczy A, Bjelik A, Baltás E, Ocsovszki I, Boda K, Penke B, Dobozy A, Kemény L, Janka Z, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Center for Medical and Pharmaceutical Sciences, University of Szeged, 6 Semmelweis Street, Szeged H-6725, Hungary. · Neurobiol Aging. · Pubmed #15961188 No free full text.

Abstract: In the present pilot investigation, the susceptibility of T-lymphocytes from Alzheimer's disease (AD) subjects (n=22) and aged-matched, non-demented controls (CNT) (n=12) was examined with ultraviolet (UV) B light-induced apoptosis in vitro. The basal apoptotic ratios were similar in both groups. However, the AD lymphocytes displayed significantly (p<0.0001) lower apoptotic levels than those of the CNT lymphocytes at all of the applied UVB exposure doses (100, 200 and 300 mJ/cm(2)). These observations indicate that AD lymphocytes are more resistant than CNT lymphocytes to UVB irradiation.

Liu Y, Walter S, Stagi M, Cherny D, Letiembre M, Schulz-Schaeffer W, Heine H, Penke B, Neumann H, Fassbender K. · Department of Neurology, University of Göttingen, Germany. · Brain. · Pubmed #15857927 links to  free full text

Abstract: The amyloid beta peptide 42 (Abeta(42)) plays a key role in neurotoxicity in Alzheimer's disease. Mononuclear phagocytes, i.e. microglia, have the potential to clear Abeta by phagocytosis. Recently, the lipopolysaccharide (LPS) receptor CD14 was shown to mediate phagocytosis of bacterial components and furthermore to contribute to neuroinflammation in Alzheimer's disease. Here, we investigated whether this key innate immunity receptor can interact with Abeta(42) and mediate phagocytosis of this peptide. Using flow cytometry, confocal microscopy and two-photon fluorescence lifetime imaging (FLIM) combined with fluorescence resonance energy transfer (FRET), we demonstrated a direct molecular interaction in the range of a few nanometers between Abeta(42) and CD14 in human CD14-transfected Chinese hamster ovary cells. Investigations using cells that were genetically deficient for this receptor showed that in <30 minutes exogenous Abeta(42) added to cultured primary microglial cells was phagocytosed into the cytoplasmic compartment in a CD14-dependent manner. This phagocytosis occurred at Abeta(42) concentration ranges that were considerably lower than the threshold to activate a cellular inflammatory reaction. In contrast, there was no association of CD14 to microglial internalization of microbeads. In complementary clinical experiments, we detected a pronounced CD14 immunoreactivity on parenchymal microglia spatially correlated to characteristic Alzheimer's disease lesion sites in brain sections of Alzheimer's disease patients but not in brain sections of control subjects. By showing a close interaction between CD14 and Abeta(42), demonstrating a direct role of CD14 in Abeta(42) phagocytosis, and detecting CD14-specific staining in brains of Alzheimer's disease patients, our results indicate a role of the LPS receptor in the pathophysiology of Alzheimer's disease, which could be of therapeutic relevance.

Datki Z, Papp R, Zádori D, Soós K, Fülöp L, Juhász A, Laskay G, Hetényi C, Mihalik E, Zarándi M, Penke B. · Department of Medical Chemistry, University of Szeged, Szeged, Hungary. · Neurobiol Dis. · Pubmed #15571986 No free full text.

Abstract: The cell biology of Alzheimer's disease (AD) is characterized mainly by the neurodegeneration caused by the beta-amyloid (Abeta) peptides and by the formation of neurofibrillary tangles. The initial events of neurodegeneration in the brain tissue include synaptic dysfunction and axonopathy. Abeta-induced axonopathy and neurite degeneration were studied in vitro on differentiated human-derived neurotypic SH-SY5Y cells. Different methods were used to investigate the mechanism of action of aggregated Abeta on neuroblastoma cells. Abeta 1-42 aggregated for 1 h induced irreversible changes in the neurite morphology. Change of tau hyperphosphorylation and cell viability (cytoplasmic redox state and active membrane uptake) was irreversible during the first hour after the addition of Abeta 1-42 to the cells. These rapid events indicate that Abeta might induce neurodegeneration even at an early stage of Abeta-cell contact. A novel pentapeptide LPYFD-amide, an analog of Soto's LPFFD, significantly decreased neurite degeneration, tau aggregation, and cell viability reduction induced by Abeta 1-42.

Palotás A, Puskás LG, Kitajka K, Palotás M, Molnár J, Pákáski M, Janka Z, Penke B, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Semmelweis u. 6, Hungary. · Eur J Pharmacol. · Pubmed #15336942 No free full text.

Abstract: Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. We have demonstrated that gene expression profiles of lymphocytes from patients with Alzheimer dementia differ from that seen with controls, with alpha(2)-adrenoceptor being the most highly repressed transcript. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer patients and control individuals to assess the impact of mirtazapine, the novel antidepressant with alpha(2)-adrenoceptor antagonistic activities, on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with mirtazapine were identified and categorized based on similarities in biological functions. This analysis revealed that selected biological processes, including protein metabolism, cytoskeleton integrity, immune response, cellular plasticity, and neurotransmission, are involved in early phases of administration of this antidepressant. In addition, although it was possible to identify common targets, the expression profiles of Alzheimer lymphocytes differed mainly in their magnitude from those seen with controls. These results confirm the usefulness of the gene array approach for studying Alzheimer-specific changes in the periphery and suggest that the expression of genes of Alzheimer lymphocytes is modulated differently by mirtazapine, which correlates with the pathology.

Palotás A, Puskás LG, Kitajka K, Palotás M, Molnár J, Pákáski M, Janka Z, Penke B, Kálmán J. · Department of Psychiatry, Albert Szent-Györgyi Medical and Pharmaceutical Center, Faculty of Medicine, University of Szeged, H-6721 Szeged, Hungary. · Neurochem Res. · Pubmed #15260135 No free full text.

Abstract: Antidepressants are widely used in the treatment of mood disorders associated with dementia, however little information is available on their effect at the molecular level. In certain neurodegenerative disorders, such as in Alzheimer's disease, lymphocytes have been used to assess mirror changes that thought to occur in the brain. Gene expression profiles of lymphocytes from Alzheimer patients have been shown to differ from that seen with controls. To address this issue in light of antidepressant treatment, we used lymphocytes derived from Alzheimer's disease patients and control individuals to assess the impact of the selective serotonine reuptake inhibitor citalopram on gene expression using a cDNA microarray representing 3200 distinct human genes. Sequences that are differentially regulated after treatment with citalopram were identified and categorized based on similarities in biological functions. This analysis revealed that the overexpression of genes in control and Alzheimer white blood cells by citalopram are implicated in cell survival. Apart from this, citalopram did not markedly alter genes involved in other molecular functions in control cells. In contrast, alteration of genes implicated in ionic currents, cell-adhesion, immune mechanism, and adrenergic functions, were also observed in Alzheimer lymphocytes. The expression of genes of Alzheimer lymphocytes by citalopram is modulated differently which may correlate with the pathology.

Palotás A, Penke B, Palotás M, Kenderessy AS, Kemény L, Kis E, Vincze G, Janka Z, Kálmán J. · Department of Medical Chemistry, University of Szeged, Szeged, Hungary. · Skin Pharmacol Physiol. · Pubmed #15258451 No free full text.

Abstract: BACKGROUND: Antipsychotics are widely used in the treatment of behavioral and psychological symptoms of dementia. A low frequency of Alzheimer's disease in patients with schizophrenia is reported, and it has been proposed that antipsychotic medications, such as haloperidol, may be responsible. Disruption of intracellular calcium levels is considered to play a key role in beta-amyloid-induced neurotoxicity in Alzheimer's disease. Haloperidol has also been reported to interact with calcium homeostasis through dopamine-2 and sigma-1 receptors, and other, yet unknown mechanisms. OBJECTIVE: Therefore, we investigated whether differences in the basal intracellular free calcium levels of cultured cutaneous fibroblasts--cells that do not express dopamine-2 and sigma-1 receptors--derived from sporadic Alzheimer patients and from age-matched control individuals after haloperidol treatment might be present. METHODS: Intracellular calcium level was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. RESULTS: Alzheimer cells exhibited significantly lower calcium level as compared to the control cultures. Exposure of fibroblasts to beta-amyloid peptide resulted in increased calcium concentration of the control cells, but not of Alzheimer fibroblasts. Co-incubation of cultures with a therapeutic dose of haloperidol blocked the beta-amyloid-induced elevation of calcium. CONCLUSION: This finding indicates that haloperidol efficiently countervails ionic imbalance and suggests that it may serve as a potential agent in alleviating neurotoxic effects of beta-amyloid peptide.

Kálmán J, Juhász A, Janka Z, Rakonczay Z, Abrahám G, Boda K, Farkas T, Penke B. · No affiliation provided · Atherosclerosis. · Pubmed #15177135 No free full text.

This publication has no abstract.

Fassbender K, Walter S, Kühl S, Landmann R, Ishii K, Bertsch T, Stalder AK, Muehlhauser F, Liu Y, Ulmer AJ, Rivest S, Lentschat A, Gulbins E, Jucker M, Staufenbiel M, Brechtel K, Walter J, Multhaup G, Penke B, Adachi Y, Hartmann T, Beyreuther K. · Department of Neurology, University of Goettingen, 37075 Goettingen, FRG. · FASEB J. · Pubmed #14597556 links to  free full text

Abstract: To rapidly respond to invading microorganisms, humans call on their innate immune system. This occurs by microbe-detecting receptors, such as CD14, that activate immune cells to eliminate the pathogens. Here, we link the lipopolysaccharide receptor CD14 with Alzheimer's disease, a severe neurodegenerative disease resulting in dementia. We demonstrate that this key innate immunity receptor interacts with fibrils of Alzheimer amyloid peptide. Neutralization with antibodies against CD14 and genetic deficiency for this receptor significantly reduced amyloid peptide induced microglial activation and microglial toxicity. The observation of strongly enhanced microglial expression of the LPS receptor in brains of animal models of Alzheimer's disease indicates a clinical relevance of these findings. These data suggest that CD14 may significantly contribute to the overall neuroinflammatory response to amyloid peptide, highlighting the possibility that the enormous progress currently being made in the field of innate immunity could be extended to research on Alzheimer's disease.

Palotás A, Kálmán J, Palotás M, Matin K, Szentpáli K, Paszt A, Janka Z, Penke B. · Department of Medical Chemistry, University of Szeged, H-6721 Szeged, Dóm tér 8, Hungary. · Neurochem Res. · Pubmed #12515309 No free full text.

Abstract: Beta-amyloid peptide plays a crucial role in the pathology of Alzheimer's disease. As part of our ongoing fluorimetric studies, in the present report we demonstrate differences in resting intracellular free calcium levels of cells in the blood derived from sporadic Alzheimer patients and from age-matched control individuals. Calcium levels were measured in Fura-2AM-loaded human blood samples by dual-wavelength spectrofluorimetry. The resting calcium concentrations of blood samples from Alzheimer patients were lower compared to that of the control samples. Exposure of control blood samples to beta-amyloid caused an increase in the calcium level. Specimens from Alzheimer donors, however, appeared to be resistant to the peptide. This simple finding may serve as a springboard to monitoring Alzheimer pathology in the peripheral systems of the body.