Altered synaptic function in Alzheimer's disease

Bell, Karen; Cuello, A. Claudio

doi:10.1016/j.ejphar.2006.06.045

Cited by 97 publications

(76 citation statements)

References 143 publications

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“…The "amyloid" hypothesis states that the toxic action of A␤ on synaptic function is responsible for memory loss (LaFerla and Oddo, 2005;Bell and Cuello, 2006). This hypothesis is supported by analysis of transgenic mice overexpressing human FAD mutations, which display A␤ accumulation and plaque formation correlating with hippocampal-dependent memory deficits (Duyckaerts et al, 2008).…”

Section: Introductionmentioning

confidence: 66%

Transgenic Mice with Chronic NGF Deprivation and Alzheimer's Disease-Like Pathology Display Hippocampal Region-Specific Impairments in Short- and Long-Term Plasticities

Houeland¹,

Romani²,

Marchetti³

et al. 2010

J. Neurosci.

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The etiology of Alzheimer's disease (AD) remains elusive. The "amyloid" hypothesis states that toxic action of accumulated ␤-amyloid peptide (A␤) on synaptic function causes AD cognitive decline. This hypothesis is supported by analysis of familial AD (FAD)-based transgenic mouse models, where altered amyloid precursor protein (APP) processing leads to A␤ accumulation correlating with hippocampal-dependent memory deficits. Some studies report prominent dentate gyrus (DG) glutamatergic plasticity alterations in these mice, while CA1 plasticity remains relatively unaffected. The "neurotrophic unbalance" hypothesis, on the other hand, states that AD-related loss of cholinergic signaling and altered APP processing are due to alterations in nerve growth factor (NGF) trophic support. This hypothesis is supported by analysis of the AD11 mouse, which exhibits chronic NGF deprivation during adulthood and displays AD-like pathology, including A␤ accumulation and hippocampal-dependent memory deficits. In this study, we analyzed CA1 and DG glutamatergic plasticity in AD11 mice to evaluate whether these mice also share with FAD models a common phenotype in hippocampal synaptic dysfunction. We report that AD11 mice display age-dependent short-and long-term DG plasticity deficits, while CA1 plasticity remains relatively spared. We also report that both structures exhibit enhanced glutamatergic transmission under lower, yet physiological, neurotransmitter release conditions, a defect that should be considered when further evaluating hippocampal synaptic deficits underlying AD pathology. We conclude that severe deficits in DG plasticity represent another common denominator between these two etiologically different types of AD mouse models, independent of the initial insult (overexpression of FAD mutation or NGF deprivation).

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Section: Introductionmentioning

confidence: 66%

Transgenic Mice with Chronic NGF Deprivation and Alzheimer's Disease-Like Pathology Display Hippocampal Region-Specific Impairments in Short- and Long-Term Plasticities

Houeland¹,

Romani²,

Marchetti³

et al. 2010

J. Neurosci.

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“…AD has been associated with an impairment of cholinergic terminals, which appear largely vulnerable, followed by glutamatergic terminal dysfunction and finally by the lesion of the somewhat more resilient GABAergic terminals (Bell and Claudio, 2006).…”

Section: Introductionmentioning

confidence: 99%

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

Mota¹,

Ferreira²,

Rego³

2014

Neuropharmacology

173

100

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Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly.Alterations capable of causing brain circuitry dysfunctions in AD may take several years to develop. Oligomeric amyloid-beta peptide (Aβ) plays a complex role in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in this devastating disease. Moreover, N-methyl-D-aspartate (NMDA) receptors (NMDARs) activation has been recently implicated in AD-related synaptic dysfunction. Thus, in this review we focus on glutamatergic neurotransmission impairment and the changes in NMDAR regulation in AD, following the description on the role and location of NMDARs at pre-and post-synaptic sites under physiological conditions. In addition, considering that there is currently no effective ways to cure AD or stop its progression, we further discuss the relevance of NMDARs antagonists to prevent AD symptomatology. This review posits additional information on the role played by Aβ in AD and the importance of targeting the tripartite glutamatergic synapse in early asymptomatic and possible reversible stages of the disease through preventive and/or disease-modifying therapeutic strategies.

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“…37,38 Studies from animal models of Alzheimer disease have shown that upregulation of cholinergic presynaptic boutons occurs before the involvement of glutamatergic terminals, thus raising the possibility that a compromised cholinergic system may affect the functioning/survival of glutamatergic neurons in the brain. 39 Indeed, pyramidal neurons of the cortex that use glutamate as their primary transmitter are known to possess both cholinergic and glutamatergic receptors and receive inputs from the basal forebrain cholinergic neurons. 35 There is evidence that cholinesterase inhibitors can promote the release of glutamate from pyramidal neurons, possibly by increasing cortical acetylcholine levels and subsequent activation of the cholinergic receptors.…”

Section: Introductionmentioning

confidence: 99%