Article

APP Processing and Synaptic Function

Johns Hopkins University, Baltimore, Maryland, United States
Neuron (Impact Factor: 15.05). 04/2003; 37(6):925-37. DOI: 10.1016/S0896-6273(03)00124-7
Source: PubMed

ABSTRACT

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.

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    • "Synaptic damage has been extensively studied in Alzheimer's disease (AD; reviewed by[1]) because in this neurodegenerative disorder the loss of synapses is the best correlate to the cognitive deficits[2,3]. Moreover, amyloid beta (Ab) oligomers appear to be formed and transported at the synapses and interfere with glutamate receptors[4,5]and synaptic functioning by interactions with presynaptic and postsynaptic receptors such as EphA[6], EphB2[7], PrPc[8], mGluR5[9], NMDA-R[10], frizzled, insulin-R, and NGF-R among others[11]. The loss of synapses in AD and other neurodegenerative disorders is most likely part of a spectrum of alterations and pathogenic molecular cascades which begins with alterations in the synaptic vesicle machinery and glutamate receptors, progressing to mitochondrial dysfunction, reduced axonal flow, and loss of neurotrophic support[12]. "
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    ABSTRACT: Introduction: Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid-β appears to contribute synaptic pathology. Although a number of clinical pathologic studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. Methods: We identified 417 publications reporting postmortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of subselected publications and calculating the standard mean differences. Results: Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that presynaptic makers were affected more than postsynaptic markers. Discussion: The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors, and axonal transport are often affected.
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    • "This last observation complements data showing that enhanced Aβ secretion upon synaptic activation requires endocytosis (Cirrito et al., 2008). Therefore, a production of Aβ might occur at synapses with activity, as also supported by increased levels of β- C-terminal fragments (βCTFs; Kamenetz et al., 2003; Tampellini et al., 2009). Activity-dependent Aβ secretion has been observed in patients after brain injury: Aβ levels were reduced in the interstitial fluid (ISF) with worsened neurological status, and increased with improved neurological condition (Brody et al., 2008). "

    Full-text · Dataset · Nov 2015
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    • "This last observation complements data showing that enhanced Aβ secretion upon synaptic activation requires endocytosis (Cirrito et al., 2008). Therefore, a production of Aβ might occur at synapses with activity, as also supported by increased levels of β- C-terminal fragments (βCTFs; Kamenetz et al., 2003; Tampellini et al., 2009). Activity-dependent Aβ secretion has been observed in patients after brain injury: Aβ levels were reduced in the interstitial fluid (ISF) with worsened neurological status, and increased with improved neurological condition (Brody et al., 2008). "
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    ABSTRACT: Synapses have been known for many years to be the crucial target of pathology in different forms of dementia, in particular Alzheimer's disease (AD). Synapses and their appropriate activation or inhibition are fundamental for the proper brain function. Alterations in synaptic/neuronal activity and brain metabolism are considered among the earliest symptoms linked to the progression of AD, and lead to a central question in AD research: what is the role played by synaptic activity in AD pathogenesis? Intriguingly, in the last decade, important studies demonstrated that the state of activation of synapses affects the homeostasis of beta-amyloid (Aβ) and tau, both of which aggregate and accumulate during AD, and are involved in neuronal dysfunction. In this review we aim to summarize the up-to-date data linking synaptic/neuronal activity with Aβ and tau; moreover, we also intend to provide a critical overview on brain activity alterations in AD, and their role in the disease's pathophysiology.
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