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A focus on the synapse for neuroprotection in Alzheimer disease and other dementias

Center for Aging and Developmental Biology, University of Rochester School of Medicine, Rochester, NY 14642-8673, USA.
Neurology (Impact Factor: 8.3). 11/2004; 63(7):1155-62. DOI: 10.1212/WNL.64.11.1991
Source: PubMed

ABSTRACT 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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    • "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 · 4.30 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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    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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    • "All these data suggested that physiological level of testosterone is likely to reduce the chance of developing AD. Preventing the loss or degeneration of synapse at early phase of AD is important [1] [22]. Since it has been suggested that testosterone is neuroprotective and prevents neurodegeneration , it is reasonable to speculate that testosterone may elicit a protective role in synapse. "
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    ABSTRACT: Increasing lines of evidence support that testosterone may have neuroprotective effects. While observational studies reported an association between higher bioavailable testosterone or brain testosterone levels and reduced risk of Alzheimer's disease (AD), there is limited understanding of the underlying neuroprotective mechanisms. Previous studies demonstrated that testosterone could alleviate neurotoxicity induced by β-amyloid (Aβ), but these findings mainly focused on neuronal apoptosis. Since synaptic dysfunction and degeneration are early events during the pathogenesis of AD, we aim to investigate the effects of testosterone on oligomeric Aβ-induced synaptic changes. Our data suggested that exposure of primary cultured hippocampal neurons to oligomeric Aβ could reduce the length of neurites and decrease the expression of presynaptic proteins including synaptophysin, synaptotagmin, and synapsin-1. Aβ also disrupted synaptic vesicle recycling and protein folding machinery. Testosterone preserved the integrity of neurites and the expression of presynaptic proteins. It also attenuated Aβ-induced impairment of synaptic exocytosis. By using letrozole as an aromatase antagonist, we further demonstrated that the effects of testosterone on exocytosis were unlikely to be mediated through the estrogen receptor pathway. Furthermore, we showed that testosterone could attenuate Aβ-induced reduction of HSP70, which suggests a novel mechanism that links testosterone and its protective function on Aβ-induced synaptic damage. Taken together, our data provide further evidence on the beneficial effects of testosterone, which may be useful for future drug development for AD.
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