Alzheimer Disease: Laskay G

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, Kálmán J, Laskay G, Juhász A, Janka Z, Penke B. · Szegedi Tudományegyetem, Orvosi Vegytani Intézet, 6721 Szeged. · Ideggyogy Sz. · Pubmed #12122875 No free full text.

Abstract: RATIONALE: beta-amyloid peptides, comprising the major neuropathological lesions of Alzheimer's disease, have been found to form depositions in various peripheral tissues, including the skin. Neurons in the disorder succumb to the altered ionic homeostasis and some other factors caused by this toxic peptide. In line with these findings, our study aimed to find differences in biochemical processes of cultured cutaneous fibroblasts derived from sporadic Alzheimer patients and from age-matched control individuals that may mirror changes in the central nervous system. METHODS: Intracellular ionic homeostasis of Alzheimer and control fibroblasts was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. RESULTS: Cells derived from Alzheimer patients exhibited lower intracellular free calcium levels as compared to the control cultures. Exposure of fibroblasts to beta-amyloid resulted in increased calcium concentrations of the control cells, but not of Alzheimer ones. CONCLUSION: Our findings indicate that Alzheimer's disease is a systemic disorder that, among others, affects the calcium homeostasis of fibroblasts. Even though it is unknown whether the diminished ionic response of Alzheimer fibroblasts is a disease or actual status marker, it could prove to be a useful model for the analysis of Alzheimer specific changes.

Palotás A, Kálmán J, Laskay G, Juhász A, Janka Z, Penke B. · Department of Medical Chemistry, University of Szeged, Hungary. · Neurochem Res. · Pubmed #11565613 No free full text.

Abstract: The accumulation of the beta-amyloid peptide (betaAP) in the brain, produced from the ubiquitously expressed amyloid precursor protein (APP) is a defining feature of Alzheimer's disease (AD). Consistent with studies demonstrating the importance of skin biopsy in the diagnosis of neurodegenerative disorders, we investigated whether differences in intracellular free calcium levels ([Ca2+]i) of cultured cutaneous fibroblasts derived from sporadic AD patients and from age-matched control individuals might be present. [Ca2+]i was measured in Fura-2AM-loaded human fibroblasts by dual wavelength spectrofluorimetry. AD cells exhibited lower [Ca2+]i as compared to the control cultures. Exposure of fibroblasts to betaAP resulted in increased [Ca2+]i of the control cells, but not of AD fibroblasts. Our test could prove useful in supporting the diagnosis of (sporadic) AD in patients suspected of suffering from the disease.

Harkany T, Abrahám I, Timmerman W, Laskay G, Tóth B, Sasvári M, Kónya C, Sebens JB, Korf J, Nyakas C, Zarándi M, Soós K, Penke B, Luiten PG. · Department of Animal Physiology, Biological Center, University of Groningen, Kerklaan 30, NL-9750 AA Haren, The Netherlands. · Eur J Neurosci. · Pubmed #10971616 No free full text.

Abstract: Whereas a cardinal role for beta-amyloid protein (Abeta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which Abeta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Abeta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of Abeta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo Abeta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. Abeta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the Abeta injection area, as was demonstrated by 45Ca2+ autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the Abeta-induced toxic insult. Such a sequence of Abeta toxicity was effectively antagonized by the N-methyl-D-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, Abeta toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that Abeta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.