Coleman P, Federoff H, Kurlan R. A focus on the synapse for neuroprotection in Alzheimer disease and other dementias. Neurology 63: 1155-1162

Center for Aging and Developmental Biology, University of Rochester School of Medicine, Rochester, NY 14642-8673, USA.
Neurology (Impact Factor: 8.29). 11/2004; 63(7):1155-62. DOI: 10.1212/WNL.64.11.1991
Source: PubMed


Synaptic dysfunction and failure are processes that occur early in Alzheimer disease (AD) and are important targets for protective treatments to slow AD progression and preserve cognitive and functional abilities. Synaptic loss is the best current pathologic correlate of cognitive decline, and synaptic dysfunction is evident long before synapses and neurons are lost. Once synaptic function fails, even in the setting of surviving neurons, there may be little chance of effectively interfering with the disease process. This review emphasizes the importance of preserving synaptic structure and function (i.e., "synaptoprotection") in AD. Such "synaptoprotective" therapy will probably need to be administered at a critical early time point, perhaps years before onset of clinical symptoms.

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    • "Astroglial atrophy may be directly linked to a reduction of astroglial homeostatic support, which may have dire consequences for performance and survival of neurones as well as may affect functional activity of synapses. All of this can result in trimming synaptic contacts, affecting transmission and weakening synaptic plasticity, which are precisely the early pathological events observed in AD (Terry, 2000; Coleman et al., 2004); a decrease in synaptic densities has been reported to correlate with the severity of dementia (DeKosky and Scheff, 1990; Samuel et al., 1994). Astrocytes support synaptic transmission through multiple mechanisms (Verkhratsky and Nedergaard, in press). "
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    ABSTRACT: Astrocytes are fundamental for homoeostasis, defence and regeneration of the central nervous system. Loss of astroglial function and astroglial reactivity contribute to the ageing of the brain and to neurodegenerative diseases. Changes in astroglia in ageing and neurodegeneration are highly heterogeneous and region-specific. In animal models of Alzheimer's disease (AD) astrocytes undergo degeneration and atrophy at the early stages of pathological progression, which possibly may alter homeostatic reserve of the brain and contribute to early cognitive deficits. At the later stages of AD reactive astrocytes are associated with neurite plaques, the future commonly found in animal models and in human diseased tissue. In animal models of the AD reactive astrogliosis develops in some (e.g. in the hippocampus) but not in all regions of the brain. For instance, in entorhinal and prefrontal cortex astrocytes to not mount gliotic response to emerging β-amyloid deposits. This deficits in reactivity coincides with higher vulnerability of these regions to AD-type pathology. Astroglial morphology and function can be regulated through environmental stimulation and/or medication suggesting that astrocytes can be regarded as a target for therapies aimed at prevention and cure of neurodegenerative disorders. Copyright © 2015. Published by Elsevier Ltd.
    Neuroscience 01/2015; DOI:10.1016/j.neuroscience.2015.01.007 · 3.36 Impact Factor
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    • "Neuropathological hallmarks of AD include brain atrophy, initially in the entorhinal and transentorhinal cortices and progressing to the whole hippocampus (Laakso et al., 2000; Raji et al., 2009; Evans et al., 2010), increased b-amyloid peptide (Ab) load and the presence of amyloid plaques (Hyman et al., 2012), intraneuronal accumulation of hyperphosphorylated/aggregated tau proteins (Sergeant et al., 2008), and neuroinflammation (Wyss-Coray and Rogers , 2012). Synaptic dysfunction, which occurs early in AD, is generally believed to be an essential event underlying the cognitive deficits associated with the disease (Coleman et al., 2004). Whereas AD so far is not curable, there is a crucial need for developing and characterizing relevant animal models to facilitate translational research. "
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    ABSTRACT: The multifactorial causes impacting the risk of developing sporadic forms of Alzheimer's disease (AD) remain to date poorly understood. Epidemiologic studies in humans and research in rodents have suggested that hypothyroidism could participate in the etiology of AD. Recently, we reported that adult-onset hypothyroidism in rats favors β-amyloid peptide production in the hippocampus. Here, using the same hypothyroidism model with the antithyroid molecule propythiouracyl, we further explored AD-related features, dysfunctional cell-signaling mechanisms and hippocampal-dependent learning and memory. In vivo MRI revealed a progressive decrease in cerebral volume of propythiouracyl-treated rats. In the hippocampus, hypothyroidism resulted in Tau hyperphosphorylation and increases in several pro-inflammatory cytokines. These modifications were associated with impaired spatial memory and reduced hippocampal expression of signaling molecules important for synaptic plasticity and memory, including neurogranin, CaMKII, ERK, GSK3β, CREB and expression of the transcription factor EGR1/Zif268. These data strengthen the idea that hypothyroidism represents an important factor influencing the risk for developing sporadic forms of AD. © 2014 Wiley Periodicals, Inc.
    Hippocampus 11/2014; 24(11). DOI:10.1002/hipo.22319 · 4.16 Impact Factor
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    • "All these changes are likely to weaken synaptic transmission and affect synaptic plasticity , and thereby being responsible for initial cognitive deficiency observed during the early stages of AD. These early cognitive deficits are the very first symptoms of AD, which start to develop years before the occurrence of specific histopathology (Terry 2000; Coleman et al. 2004). Weakening of cognitive abilities reflects in reduced synaptic connectivity due to decreased synaptic function and synaptic loss. "
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    ABSTRACT: Abstract Neurodegenerative diseases, which affect almost exclusively humans, are chronic disorders that ultimately result in atrophy of the brain and profound cognitive deficit. Neurodegenerative process reflects a profound failure of brain homeostasis. Neuroglial cells, being primarily the cells responsible for brain homeostasis and defense, naturally contribute to an overall homeostatic failure underlying neurodegeneration. In this chapter we shall deliver a brief on astroglial contribution to common neurodegenerative disorders and then continue with a detailed account on the pathological potential of astroglia in Alzheimer’s disease. Astrocytes undergo complex alterations in Alzheimer’s disease, which are represented by region-specific atrophy and asthenia at the early stages and reactivity at the late stages of the disease. These complex changes can be considered as pathologically relevant because they may define the early cognitive deficits and the later neurotoxicity in Alzheimer’s disease. Targeting astroglia in neurodegeneration may result in new therapeutic strategies aimed at preventing and delaying the progression of Alzheimer’s disease.
    Pathological Potential of Neuroglia. Possible New Targets for Medical Intervention, Edited by Alexei Verkhratsky, Vladimir Parpura, 09/2014: chapter Neurodegeneration and Neuroglia: Emphasis on Astroglia in Alzheimer’s Disease: pages 265 - 292; Springer., ISBN: 978-1-4939-0973-5
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