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.

Download full-text


Available from: Jee Hoon Roh, Dec 28, 2013
18 Reads
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    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.
    Neuron 03/2015; 85(5):901-910. DOI:10.1016/j.neuron.2014.12.063 · 15.05 Impact Factor
  • Source
    • "Such changes in neural efficiency have been interpreted as a form of neural compensation to maintain an equivalent level of performance to that of noncarriers. However, the overuse of neural compensatory mechanisms in early adulthood might indirectly potentiate Ab production, as Ab levels are strongly regulated by neuronal activity (Cirrito et al., 2005; Bero et al., 2011); which, in turn, could diminish the functional capacity of the brain to compensate for the reduced efficiency produced by AD pathology in medial regions of the temporal lobe (Alexander et al., 2012). Then, a reduction of processing capacity could explain why associative memory in aMCI E4 carriers does not improve under conditions of semantic congruency. "
    [Show abstract] [Hide abstract]
    ABSTRACT: People with amnestic mild cognitive impairment (aMCI), compared to healthy older adults (HO), benefit less from semantic congruent cues during episodic encoding. The presence of the apolipoprotein E (APOE) ε4 makes this congruency benefit smaller, but the neural correlates of this deficit are unknown. Here, we estimated the source generators of EEG oscillatory activity associated with successful encoding of face-location associations preceded by semantically congruent and incongruent cues in HO (N = 26) and aMCI subjects (N = 34), 16 of which were ε4 carriers (ε4+) and 18 ε4 noncarriers (ε4-). Source estimation was performed in those spectro-temporal windows where the power of low-alpha, high-alpha and beta oscillatory activity differed either between congruent and incongruent faces or between groups. Differences in high-alpha and beta-oscillatory dynamics indicated that aMCI ε4+ are unable to activate lateral regions of the temporal lobe involved in associative memory and congruency benefit in HO. Interestingly, and regardless of APOE genotype, aMCI activated additional regions relative to HO, through alpha oscillations. However, only activation in a distributed fronto-temporo-parietal network in ε4 noncarriers was paralleled by enhanced memory. On the contrary, the redundant prefrontal activation shown by aMCI ε4+ did not prevent performance from decreasing. These results indicate that the effect of aMCI-related degeneracy on functional networks is constrained by the presence of APOE ε4. Whereas individuals with aMCI ε4- activate attentional, perceptual and semantic compensatory networks, aMCI ε4+ show reduced processing efficiency and capacity. This article is protected by copyright. All rights reserved.
    Hippocampus 01/2015; 25(9). DOI:10.1002/hipo.22422 · 4.16 Impact Factor
  • Source
    • "Animal experiments show that interstitial concentration of amyloid beta (Aß) increases with synaptic activity (Bero et al., 2011; Cirrito et al., 2005). Diurnal fluctuation of cerebrospinal fluid Aß42 in humans peaks in the evening and decreases at night, supporting a relationship to neuronal activity (Kang et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose One of the interesting features of the amyloid tracer Pittsburgh compound B (PiB) is that it generates a signal in the white matter (WM) in both healthy subjects and cognitively impaired individuals. This characteristic gave rise to the possibility that PiB could be used to trace WM pathology. In a group of cognitively healthy elderly we examined PiB retention in normal-appearing WM (NAWM) and WM lesions (WML), one of the most common brain pathologies in aging. Methods We segmented WML and NAWM on fluid attenuation inversion recovery (FLAIR) images of 73 subjects (age 61.9 ± 10.0, 71 % women). PiB PET images were corrected for partial volume effects and coregistered to FLAIR images and WM masks. WML and NAWM PiB signals were then extracted. Results PiB retention in WML was lower than in NAWM (p
    European journal of nuclear medicine and molecular imaging 10/2014; 42(1). DOI:10.1007/s00259-014-2897-1 · 5.38 Impact Factor
Show more