Alzheimer Disease: Verkhratsky A

Rodríguez JJ, Olabarria M, Chvatal A, Verkhratsky A. · Faculty of Life Sciences, The University of Manchester, Manchester, UK. · Cell Death Differ. · Pubmed #19057621 No free full text.

Abstract: Astrocytes, the most numerous cells in the brain, weave the canvas of the grey matter and act as the main element of the homoeostatic system of the brain. They shape the microarchitecture of the brain, form neuronal-glial-vascular units, regulate the blood-brain barrier, control microenvironment of the central nervous system and defend nervous system against multitude of insults. Here, we overview the pathological potential of astroglia in various forms of dementias, and hypothesise that both atrophy of astroglia and reactive hypertrophic astrogliosis may develop in parallel during neurodegenerative processes resulting in dementia. We also show that in the transgenic model of Alzheimer's disease, reactive hypertrophic astrocytes surround the neuritic plaques, whereas throughout the brain parenchyma astroglial cells undergo atrophy. Astroglial atrophy may account for early changes in synaptic plasticity and cognitive impairments, which develop before gross neurodegenerative alterations.

Verkhratsky A. · Faculty of Life Sciences, the University of Manchester, Manchester, UK. · Acta Pharmacol Sin. · Pubmed #16787559 links to  free full text

Abstract: Neuronal-glial circuits underlie integrative processes in the nervous system. Function of glial syncytium is, to a very large extent, regulated by the intracellular calcium signaling system. Glial calcium signals are triggered by activation of multiple receptors, expressed in glial membrane, which regulate both Ca2+ entry and Ca2+ release from the endoplasmic reticulum. The endoplasmic reticulum also endows glial cells with intracellular excitable media, which is able to produce and maintain long-ranging signaling in a form of propagating Ca2+ waves. In pathological conditions, calcium signals regulate glial response to injury, which might have both protective and detrimental effects on the nervous tissue.

Verkhratsky A, Toescu EC. · The University of Manchester, School of Biological Sciences, Manchester, United Kingdom. · J Cell Mol Med. · Pubmed #14754504 No free full text.

Abstract: The endoplasmic reticulum (ER) is a universal signalling organelle, which regulates a wide range of neuronal functional responses. Calcium release from the ER underlies various forms of intracellular Ca(2+) signalling by either amplifying Ca(2+) entry through voltage-gated Ca(2+) channels by Ca(2+)-induced Ca(2+) release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca(2+) release (IICR). The ER Ca(2+) store emerges as a single interconnected pool, thus allowing for a long-range Ca(2+) signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca(2+) concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca(2+) homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca(2+) handling may be involved in pathogenesis of various neurodegenerative diseases including brain ischemia and Alzheimer dementia.

Toescu EC, Verkhratsky A. · Department of Physiology, The University of Birmingham, B15 2TT Edgbaston, UK. · Cell Calcium. · Pubmed #12909078 No free full text.

Abstract: The nature of brain ageing and the age-dependent decline in cognitive functions remains poorly understood. Physiological brain ageing is characterised by mild mental dysfunctions, whereas age-dependent neurodegeneration, as illustrated by Alzheimer disease (AD), results rapidly in severe dementia. These two states of the aged brain, the physiological and the pathological, are fundamentally different as the latter stems from significant neuronal loss, whereas the former develops without significant neuronal demise. In this paper, we review the changes in neuronal Ca(2+) homeostasis that occur during brain ageing, and conclude that normal, physiological ageing is characterised mainly by a decrease of neuronal homeostatic reserve, defined as the capacity to respond effectively to functional and metabolic stressors, but does not reach the trigger required to induce neuronal death. In contrast, during neurodegenerative states, Ca(2+) homeostasis is affected early during the pathological process and result in significant neuronal demise. We also review recent evidence suggesting that the endoplasmic reticulum (ER) might play an important role in controlling the balance between healthy and pathological neuronal ageing.

Rodríguez JJ, Jones VC, Tabuchi M, Allan SM, Knight EM, LaFerla FM, Oddo S, Verkhratsky A. · Faculty of Life Sciences, The University of Manchester, Manchester, United Kingdom. · PLoS One. · Pubmed #18698410 links to  free full text

Abstract: It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (beta-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of beta-amyloid plaques and an increase in the number of beta-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment.

Cole AR, Noble W, van Aalten L, Plattner F, Meimaridou R, Hogan D, Taylor M, LaFrancois J, Gunn-Moore F, Verkhratsky A, Oddo S, LaFerla F, Giese KP, Dineley KT, Duff K, Richardson JC, Yan SD, Hanger DP, Allan SM, Sutherland C. · Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK. · J Neurochem. · Pubmed #17683481 No free full text.

Abstract: Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that can regulate microtubule assembly in neurons. This function of CRMP2 is regulated by phosphorylation by glycogen synthase kinase 3 (GSK3) and cyclin-dependent kinase 5 (Cdk5). Here, using novel phosphospecific antibodies, we demonstrate that phosphorylation of CRMP2 at Ser522 (Cdk5-mediated) is increased in Alzheimer's disease (AD) brain, while CRMP2 expression and phosphorylation of the closely related isoform CRMP4 are not altered. In addition, CRMP2 phosphorylation at the Cdk5 and GSK3 sites is increased in cortex and hippocampus of the triple transgenic mouse [presenilin-1 (PS1)(M146V)KI; Thy1.2-amyloid precursor protein (APP)(swe); Thy1.2tau(P301L)] that develops AD-like plaques and tangles, as well as the double (PS1(M146V)KI; Thy1.2-APP(swe)) transgenic mouse. The hyperphosphorylation is similar in magnitude to that in human AD and is evident by 2 months of age, ahead of plaque or tangle formation. Meanwhile, there is no change in CRMP2 phosphorylation in two other transgenic mouse lines that display elevated amyloid beta peptide levels (Tg2576 and APP/amyloid beta-binding alcohol dehydrogenase). Similarly, CRMP2 phosphorylation is normal in hippocampus and cortex of Tau(P301L) mice that develop tangles but not plaques. These observations implicate hyperphosphorylation of CRMP2 as an early event in the development of AD and suggest that it can be induced by a severe APP over-expression and/or processing defect.