Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
Nature Neuroscience (Impact Factor: 16.1). 06/2011; 14(6):750-6. DOI: 10.1038/nn.2801
Source: PubMed


Amyloid-β (Aβ) plaque deposition in specific brain regions is a pathological hallmark of Alzheimer's disease. However, the mechanism underlying the regional vulnerability to Aβ deposition in Alzheimer's disease is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ, which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ concentrations in several brain regions of APP transgenic mice before plaque deposition were commensurate with the degree of subsequent plaque deposition and with the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissal stimulation increased ISF Aβ, and unilateral vibrissal deprivation decreased ISF Aβ and lactate, in contralateral barrel cortex. Long-term unilateral vibrissal deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in Alzheimer's disease.

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Available from: Jee Hoon Roh, Dec 28, 2013
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    • "These data suggest that the observed overexpression of AD-linc1 in LOAD is due to A 1-42 accumulation and open the possibility that AD-linc1 is involved in amyloid-induced neurotoxicity. Alternations of activities of specific neuronal networks during AD are thought to be important contributors to the development and progression of the pathology, in part through regional vulnerability to A deposition [75]. Differential expression of these lncRNAs in LOAD cases, tissue-specific pattern of expression and their nuclear localization suggest involvement of noncoding part of genome in complex disorders such as LOAD and warrant holistic approaches to consider these transcripts together with protein-coding genes in studies aim to understand pathological processes leading to LOAD. "
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    Full-text · Article · Sep 2015 · Journal of Alzheimer's disease: JAD
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    • "nduced dendritic spine loss and memory deficits ( Smith et al . , 2009 ; Talantova et al . , 2013 ) . On the other hand , both Aβ and APP modulate excitatory presynaptic vesicle release in an activity - dependent manner ( Abramov et al . , 2009 ; Fogel et al . , 2014 ) , whereas neuronal activity modulates generation and deposition of Aβ in vivo ( Bero et al . , 2011 ) , suggesting that neuronal hyperactivity can contribute to Aβ generation and accumulation . Taken together , these results point toward a bidirectional regulation between Aβ and neuronal activity through presynaptic and postsynaptic mechanisms . FIGURE 3 | Hypothetical model linking expression of synaptic genes and neuronal and memory"
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    ABSTRACT: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by abnormal accumulation of β-amyloid and tau and synapse dysfunction in memory-related neural circuits. Pathological and functional changes in the medial temporal lobe, a region essential for explicit memory encoding, contribute to cognitive decline in AD. Surprisingly, functional imaging studies show increased activity of the hippocampus and associated cortical regions during memory tasks in presymptomatic and early AD stages, whereas brain activity declines as the disease progresses. These findings suggest an emerging scenario where early pathogenic events might increase neuronal excitability leading to enhanced brain activity before clinical manifestations of the disease, a stage that is followed by decreased brain activity as neurodegeneration progresses. The mechanisms linking pathology with synaptic excitability and plasticity changes leading to memory loss in AD remain largely unclear. Recent studies suggest that increased brain activity parallels enhanced expression of genes involved in synaptic transmission and plasticity in preclinical stages, whereas expression of synaptic and activity-dependent genes are reduced by the onset of pathological and cognitive symptoms. Here, we review recent evidences indicating a relationship between transcriptional deregulation of synaptic genes and neuronal activity and memory loss in AD and mouse models. These findings provide the basis for potential clinical applications of memory-related transcriptional programs and their regulatory mechanisms as novel biomarkers and therapeutic targets to restore brain function in AD and other cognitive disorders.
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    • "Recent human neuroimaging data suggest that resting-state functional connectivity strength is reduced in patients with AD (Buckner et al., 2009; Gleichmann and Mattson, 2010). Interestingly, Ab deposition from interstitial fluid initially appears to be most pronounced near more functionally active networks, where it then reduces network activity (Bero et al., 2011, 2012); likewise, tau release from neurons is influenced by neuronal activity (Yamada et al., 2014). Notably, IP3 receptor signaling is dysregulated in AD model mice, and Ryanodine receptor is upregulated in AD-derived tissue, in AD mice, and upon stress, leading to enhanced release of calcium into the cytosol and decreased excitability due to activation of SK channels (Stutzmann et al., 2004, 2006; Liu et al., 2012; Demuro and Parker, 2013). "
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    ABSTRACT: Neurodegenerative diseases (NDDs) involve years of gradual preclinical progression. It is widely anticipated that in order to be effective, treatments should target early stages of disease, but we lack conceptual frameworks to identify and treat early manifestations relevant to disease progression. Here we discuss evidence that a focus on physiological features of neuronal subpopulations most vulnerable to NDDs, and how those features are affected in disease, points to signaling pathways controlling excitation in selectively vulnerable neurons, and to mechanisms regulating calcium and energy homeostasis. These hypotheses could be tested in neuronal stress tests involving animal models or patient-derived iPS cells. Copyright © 2015 Elsevier Inc. All rights reserved.
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