The Neuroscience and Neuropsychology of Aging Program of the National Institute
on Aging sponsored a satellite symposium to the 28th Annual Meeting of the
Society for Neuroscience on November 7, 1998 in Los Angeles. The topic of the
symposium was "Glial Cells in Aging and Neurodegeneration" and featured
presentations from six prominent neuroscientists.
Neuroglia and other cells, such as microglia, have been implicated in a variety of adaptive functions in
the nervous system. In addition to neuroprotective effects, these cells exhibit
neuropathological activity, such as inflammatory responses and aberrant patterns
of gene expression as found in neurodegenerative diseases. Changes in glial
cell gene expression, survival and function might contribute to enhanced
vulnerability of brain cells to excitotoxicity and age-related neuronal
dysfunction. Age-related alterations in oligodendrocytes may contribute to
dysfunctional axonal connections leading to cognitive deficits in the absence of
neuron loss. Moreover, astrocyte and microglia activation is associated with
the amyloid plaques of Alzheimer's disease suggesting that these cells and the
factors they produce actively contribute to disease progression and pathology.
This symposium highlighted recent research on the cellular and molecular changes
in glia during aging and the role of glia in the pathogenesis of
neurodegenerative disorders. Speakers included C. Cotman, M. Goldberg, W.S.T.
Griffin, G. Pasinetti, A. Peters, and J. Rothstein.
Aging, and the Neuroglial Cells in Primate Cerebral Cortex.
Alan Peters
Department of Anatomy and Neurobiology
Boston University School of Medicine, Boston, MA 02118
Abstract:
The effects of normal aging on the primate brain have been examined using a colony of rhesus monkeys (Macaca mulatta). The animals are behaviorally tested before their brains are examined and the effects of aging have been determined by comparing young (5 to 10 years) and old (over 25 years) monkeys. We, and others, have concluded that there is no significant loss of neurons from the cerebral cortex of both humans and monkeys during normal aging. Indeed, the cells that are most obviously affected by age are the neuroglial cells. However, aging does affect some cortical neurons and this is most obvious in layer 1, where dendrites in the apical tufts of pyramidal cells degenerate, leading to a decrease in the thickness of layer 1. In area 46 of prefrontal cortex this decrease in thickness correlates both with age and with the performance of the monkeys on a delayed non-matching to sample task. The thinning is accompanied by a significant loss of synapses and by astrocytosis, so that the number and thickness of astrocytic processes increases, as does the number of astroglial filaments. This is most obvious in the glial limiting membrane, which becomes greatly thickened with age. However, throughout the cortex most astrocytes in old animals contain phagocytosed material. This is also true of the microglial cells, many of which become very large due to the debris in their perikarya. But interestingly, the appearance of the inclusions within astrocytes and microglial cells is quite different.
The oligodendroglia are also affected by age, since both their perikarya and processes come to contain dense inclusion bodies. The processes can become very distended by these inclusions. These changes in the oligodendroglia are accompanied by a deterioration or breakdown of myelin sheaths. Profiles of many of the sheaths have splits that contain dark cytoplasm, while others show focal swellings, or balloons. The extent of this breakdown of the myelin correlates with increasing age, and in a study of nerve fibers in visual cortex, there is also a correlation with the behavioral ranking of the monkeys. The monkeys that display the most extensive cognitive decline are ones with the most extensive deterioration of myelin. It is suggested that the cognitive decline might be produced by the myelin breakdown affecting conduction rates along axons, so that the timing in neuronal circuits is disrupted. Supported by NIA grant 2POlAG00001
Reactive Gliosis in Alzheimer's Disease and Frontotemporal Dementia.
C.W. Cotman, C.J. Pike, J.H. Su, K.E. Nichol, and J.A. Martin.
Institute for Brain Aging & Dementia, University of California, Irvine, CA 92697-4540
- Listen
to RealAudio: Lecture
(Due to technical problems, the early portion of the talk was not recorded. Audience questions are inaudible. Our apologies.)
Abstract:
Glia beneficially modulate neuronal function and viability. In neurodegenerative diseases, altered glial functioning undoubtedly has corresponding direct and indirect effects on neurons. In Alzheimer's disease (AD) brain, glia adopt reactive states. Generalized reactive astrocytosis is observed throughout pathologically affected regions of AD brain as well as more focal and intense reaction with senile plaques. Similarly, activated microglia exhibit widespread influence and a notable presence in the senile plaque environment. Utilizing primary cell culture models, we have been studying AD-related reactive gliosis and the contribution of beta
-amyloid to these events. We have observed that aggregated beta
-amyloid fibrils induce reactive astrocytosis in vitro that is characterized by exaggerated stellate morphology, and increased expression of basic fibroblast growth factor, interleukin-1beta
, and glutamine synthetase. In cultured microglia, beta
-amyloid can induce cell death in a subpopulation of microglia consistent with the observation of microglial apoptosis in AD brain. In resistant microglia, beta
-amyloid can induce inflammatory events including oxidative bursting.
Frontotemporal dementia (FTD) is also associated with glial activation, however a different activation profile and consequent neuronal outcome is suggested. Unlike the AD brain, reactive gliosis in FTD is characterized by apparent apoptotic cell death of astrocytes and perhaps microglia as well. Increased GFAP immunoreactivity and altered morphology indicate reactive astrocytosis that is moderate in frontal cortex and severe in immediately subcortical white matter. Interestingly, some astrocytes exhibit irregular somal swelling and or apparent fragmentation of processes suggesting degeneration. Examination of sections double-labeled for GFAP and TdT reveals that the majority of morphologically degenerated GFAP-positive astrocytes colocalize with robust TdT-labeling of nuclei, perhaps indicating apoptosis. Double-immunolabeling for GFAP and caspase-3p18 (a polyclonal antibody to active caspase-3) shows active caspase-3 within the soma and processes of morphologically degenerated astrocytes. Finally, astrocytes in FTD brain exhibit decreased levels of glutamate transporter. These data suggest that as a result of glial degeneration and or activation in the FTD brain, there is an impairment in normal astrocyte functioning that may lead to deleterious effects on neurons. For example, dysregulation in glutamate metabolism resulting from depleted glial glutamate transporter may both increase the risk for neuronal excitotoxicity and disrupt normal glutamatergic neural transmission. Although the ultimate effects of glial activation in AD and FTD are unknown, it appears that there are both beneficial and deleterious effects on neurons, the cumulative effects of which likely modulate neuronal responses to disease processes.
The Role of the Cytokine Cycle in Alzheimer Pathogenesis.
W. Sue T. Griffin, Jin G. Sheng, and Robert E. Mrak. Geriatric Res. Ed. Clin. Ctr., Mental Ill. Res. Ed. Clin. Ctr., McClellan Vet. Aff. Med. Ctr.; Geriatrics and Pathol. Depts., Univ. Ark. Med. Sci., Little Rock, AR 72205
Abstract:
The role of glial inflammatory responses to neuronal injury in Alzheimer’s disease has been highlighted by recent epidemiological work implicating anti-inflammatory drugs as important ameliorating agents in this disease and establishing head trauma as an important risk factor for later development of Alzheimer’s disease. Our studies have advanced the hypothesis that chronic activation of glial inflammatory processes is engendered by genetic or environmental insults to neurons, via neuronal signaling of microglial activation and excessive elaboration of the immunomodulatory cytokine interleukin-1. This overexpression of IL-1 sets in motion a self-propagating cascade - the cytokine cycle - of cellular and molecular events with potentially beneficial neuronotrophic consequences in the short term, but potentially harmful neurodegenerative consequences in the long term. For instance, interleukin-1: i) promotes excessive synthesis and processing of the beta-amyloid precursor protein and other beta-amyloid plaque-associated proteins, and ii) activates astrocytes with promotion of astrocytic synthesis and release of a number of inflammatory and neuroactive molecules. One of these interleukin-1-regulated astrocyte-derived molecules, S100 beta, may stress neurons, perhaps old ones in particular, as it promotes neurite growth and, like interleukin-1, induces excessive synthesis of neuronal beta-amyloid precursor protein. In addition, S100-beta induces increases in intraneuronal free calcium concentrations which are neuronotoxic. The resulting neuronal injury can further activate microglia, with further overexpression of interleukin-1, and thereby produce feedback amplification of the cytokine cycle. Unremitting self-propagation of these neurodegenerative processes thus provide an explanation for the progressive nature of Alzheimer’s disease.
The Role of Neuronal Cyclooxygenase (COX)-2 Expression on Glia Activity and Neurodegeneration.
Giulio Maria Pasinetti, Neuroinflammation Research Center of the Department of Psychiatry and Brookdale Center for Molecular Biology, The Mount Sinai School of Medicine, New York, NY 10028
Abstract:
Inflammatory activity, including the accumulation of activated microglia around neuritic plaques, accompanies the neuropathology of Alzheimer's disease (AD). Epidemiological evidence suggesting a neuroprotective effect of anti-inflammatory drugs is consistent with the hypothesis that this inflammatory activity contributes to neuronal loss. A recent report that prior use of non-steroidal anti-inflammatory drugs (NSAIDs), which are inhibitors of cyclooxygenase (COX), is associated with reduction in microglial accumulation in post-mortem AD brain, further supports a link between anti-inflammatory drugs, microglia and neuronal loss in this disease. However, the surprising finding that COX-2 expression in AD brain is primarily neuronal is consistent with a neuronal, rather than microglial, target for NSAID activity in AD. Our studies have shown that COX-2 is upregulated in AD cortex, where it correlates with amyloid plaque deposition.
To clarify the role of neuronal COX-2 expression in neurodegeneration, we have generated a transgenic mouse line with neuronal overexpression of human COX-2. Preliminary evidence utilizing this model suggests that neuronal overexpression of COX-2: (1) increases beta
-amyloid peptide neurodegeneration; (2) increases the susceptibility to excitotoxic lesions; and (3) is associated with an age-dependent accumulation of brain microglia as assessed by lectin staining.
These findings are consistent with the hypothesis that neuronal COX-2 expression contributes to neurotoxic mechanisms in AD, and may involve a secondary microglial response. Inhibition of neuronal COX-2 by NSAIDs may control microglial responses, demonstrating a neuron-to-glia interaction that may be mediated by prostanoids and/or oxidants generated by COX. Supported by NIA grants AG 13799, AG 14239, AG 14766 to GMP.
Aberrant RNA Processing - A Glial Basis for Neurodegeneration.
Jeffrey D. Rothstein, Department of Neurology, Johns Hopkins University, Baltimore, MD 21287
Abstract:
Glutamate transport is essential for the synaptic inactivation of the neurotransmitter glutamate. The predominant glutamate transporter protein in the central nervous system (CNS), EAAT2, is selectively localized to astrocytes in adult CNS. Recent studies document a dramatic loss of the transporter protein in sporadic amyotrophic lateral sclerosis (ALS) and in transgenic models of inherited motor neuron disease. Multiple mechanisms could be responsible for the loss of this protein in neurodegeneration including oxidative stress and neuronal regulation. The molecular mechanism responsible for the loss of EAAT2 in ALS appears to be the aberrant formation of truncated EAAT2 RNA species. Aberrant RNA processing/metabolism in motor neuron disease will be discussed. Furthermore, these studies, and additional studies in transgenic models of ALS, suggest the possible role for abnormal astrocyte biology as a possible causal/contributing process in neurodegeneration.
Glial Excitotoxicity: Can Glutamate Mediate Cell Death of Astrocytes and Oligodendrocytes?
Mark P. Goldberg, Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110
Abstract:
Toxic overactivation of glutamate receptors, or excitotoxicity, is an important mechanism leading to neuronal death in many disease states. Although glial cells also express glutamate receptors, the role of these receptors in neurologic disease has been studied only recently. We have examined glial excitotoxicity in primary cultures of astrocytes and oligodendrocytes derived from embryonic and postnatal mouse cerebral hemispheres. Both astrocytes and oligodendrocytes express AMPA/kainate glutamate receptors, but not NMDA receptors. Cultured type 1 astrocytes are not injured even by prolonged application of large concentrations of glutamate agonists, in large part due to rapid desensitization of astrocyte AMPA receptors (David et al., J Neurosci 16: 200-209, 1996). In contrast, oligodendrocytes are highly sensitive to glutamate receptor activation. Application of AMPA results in inward ionic currents, elevation of intracellular calcium, and oligodendrocyte death after 24 hours (McDonald et al., Nature Medicine 4:291-297, 1998). AMPA receptor activation also contributes to oligodendrocyte death following transient oxygen-glucose deprivation, which can be blocked by addition of selective AMPA antagonists. In vivo, oligodendrocytes in subcortical white matter of adult rats are injured by microstereotaxic administration of AMPA but not NMDA.
These observations suggest that oligodendrocytes share with neurons a high vulnerability to excitotoxic death mediated by AMPA receptor activation. Glutamate-mediated oligodendrocyte death may contribute to white matter injury in a variety of CNS diseases, including stroke and trauma. Effective therapeutic approaches to these diseases require attention to injury in white as well as gray matter.
For further information about this symposium and the NIA's interest in
this research area, please contact:
Dr. Brad Wise
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 3C307
7201 Wisconsin Avenue MSC 9205
Bethesda, Maryland 20892-9205
Tel: 301-496-9350; Fax: 301-496-1494
Email: bw86y@nih.gov
Home
